levoleucovorin and Neoplasm-Metastasis

Doublet or triplet chemotherapy regimens in combination with anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (mAb), such as cetuximab or panitumumab, or the anti-vascular endothelial growth factor mAb bevacizumab, are the current recommended standard of care therapies for unresectable metastatic colorectal cancer (mCRC). While the recommended dosing schedule for the triplet chemotherapy regimen with 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) in combination with bevacizumab is well established, the optimal dosing of FOLFOXIRI in combination with anti-EGFR agents is unknown. Several randomized, phase 3 clinical trials of patients with mCRC have demonstrated improved survival and response rates with FOLFOXIRI, alone or when combined with bevacizumab, compared with doublet chemotherapy regimens. Trials of anti-EGFR agents in combination with FOLFOXIRI have also shown promising results. In this review, we summarize the emerging evidence regarding the safety and efficacy of anti-EGFR agents in combination with triplet chemotherapy regimens and discuss the potential for this combination as a future treatment option for patients with RAS-wild-type mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; ErbB Receptors; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic

Various first-line chemotherapy treatment regimens for patients with metastatic pancreatic cancer have been approved in Japan, including gemcitabine (GEM); fluorouracil, leucovorin, irinotecan, and oxaliplatin combination (FOLFIRINOX); GEM plus albumin-bound paclitaxel (GEM+NPTX), and S-1 (tegafur + gimeracil + oteracil). However, direct comparisons of these chemotherapy regimens are limited.. To assess the short-term and long-term outcomes associated with first-line chemotherapy regimens for metastatic pancreatic cancer compared with chemotherapy regimens recommended in Japanese guidelines.. In this systematic review and network meta-analysis, the bibliographic databases PubMed, Cochrane Library, and Web of Science, as well as medical journals published between January 1, 2002, and December 31, 2018, were searched for clinical trials comparing chemotherapy regimens.. Randomized 2-arm clinical trials evaluating first-line chemotherapy for advanced or metastatic pancreatic cancer were included.. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions was followed for data abstractions. Data were pooled using a random-effects model. The SIGN 50 Quality Assessment Instrument was used to assess the risk of bias and overall study quality of the selected trials.. The primary end point was overall survival (OS), and the secondary end point was progression-free survival (PFS) compared with GEM for first-line chemotherapy for metastatic pancreatic cancer. The Kaplan-Meier curve of GEM from the literature and the estimated hazard ratios (HRs) were used to model the long-term associations to calculate the area under the curve (AUC) (person-months) for OS and PFS of each chemotherapy. Sensitivity analyses with multiple functional models were conducted to confirm the long-term estimations.. A total of 22 regimens (25 studies) for OS and a total of 18 regimens (21 studies) for PFS were identified from literature. The total number of participants was 10 186, with 5856 male (57.5%) and 4330 female (42.5%). The FOLFIRINOX and GEM+NPTX regimens were associated with reduction in the risk of death, with an HR of 0.57 (95% CI, 0.41-0.79) and 0.72 (95% CI, 0.55-0.95) compared with GEM, respectively. The curve estimation also showed that FOLFIRINOX had the largest AUC for survival at 15.49 person-months (range, 13.84-15.51 person-months), followed by GEM+NPTX with 12.36 person-months (range, 10.98-12.59 person-months), GEM+ERLO with 10.84 person-months (range, 9.66-11.23 person-months), S-1 with 8.44 person-months (range, 8.26-9.74 person-months), and GEM with 8.10 person-months (range, 7.93-9.38 person-months).. The results of this network meta-analysis support the relative short-term and long-term outcomes associated with first-line chemotherapy for metastatic pancreatic cancer used clinically in Japan.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Comparative Effectiveness Research; Deoxycytidine; Drug Combinations; Fluorouracil; Gemcitabine; Humans; Irinotecan; Japan; Kaplan-Meier Estimate; Leucovorin; Neoplasm Metastasis; Network Meta-Analysis; Oxaliplatin; Oxonic Acid; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Proportional Hazards Models; Pyridines; Survival Rate; Tegafur; Treatment Outcome

Treatment outcomes between FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and GNP (gemcitabine with albumin-bound paclitaxel) as first-line chemotherapy regimens for metastatic pancreatic cancer (PC) were assessed according to ethnic groups categorized as Western or Asian subgroups. PubMed, EMBASE, and Cochrane library were searched. Thirteen studies were eligible in this meta-analysis. Overall survival was not significantly different between FOLFIRINOX and GNP (HR 1.00, 95% CI 0.83-1.20, P = 0.990). However, the Western subgroup showed a higher survival benefit for FOLFIRINOX over GNP (HR 0.84, 95% CI 0.74-0.95, P = 0.006) whereas the Asian subgroup showed the survival benefit for GNP over FOLFIRINOX (HR 1.29, 95% CI 1.03-1.60, P = 0.030). Progression free survival was not significantly different between the two regimens in the Western subgroup (HR 1.01, 95% CI 0.84-1.20, P = 0.950) and the Asian subgroup (HR 1.13, 95% CI 0.97-1.33, P = 0.110). Occurrence of febrile neutropenia was significantly higher in FOLFIRINOX at both ethnic subgroups; however, that of peripheral neuropathy was significantly higher only in GNP of the Asian subgroup. Therefore, pharmacoethnicity might be a factor worth considering when deciding on a frontline chemotherapeutic regimen although the overall survival was not significantly different between FOLFIRINOX and GNP for metastatic PCs.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Ethnicity; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Treatment Outcome

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Clinical Trials, Phase III as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liposomes; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

Acinar cell carcinoma of the pancreas (pACC) forms a rare subgroup of pancreatic tumors. We report on our institutional experience with systemic first- and further-line therapy in patients with metastatic pACC and embed our findings in a review of the literature.. Patients with stage IV pACC who started systemic treatment between 2008 and 2019 at our institution were identified via our institutional database. Clinical data were extracted from the patients' electronic data records. Survival times were calculated by the Kaplan-Meier method.. Six patients received a fluoropyrimidine- and oxaliplatin-containing first-line treatment, and 4 patients were started on gemcitabine-based protocols. Median progression-free survival was 4.8 months [95% confidence interval (CI), 3.3 to not available (n.a.)], and median overall survival was 15.3 months (95% CI, 10.1 to n.a.). Residual survival for second-line treatment was 2.1 months (95% CI, 1.3 to n.a.), although 1 patient experienced almost complete remission under targeted therapy.. The most encouraging and deep responses result from poly-chemotherapy with leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), which seems to be the appropriate choice in fit patients. Gemcitabine monotherapy seems without substantial activity in pACC. Whenever possible, patients with pACC should be screened for targetable mutations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Acinar Cell; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Retrospective Studies

To assess the efficacy and safety of ramucirumab in combination with FOLFIRI in patients with unresectable metastatic colorectal cancer under clinical practice in Japan, we reviewed manuscripts reporting clinical research, including case reports, of Japanese patients with FOLFIRI plus ramucirumab therapy published starting from 2016, when ramucirumab was approved as a treatment for metastatic colorectal cancer in Japan, to June 2020. We also reviewed an interim report of post-marketing surveillance study. The efficacy of ramucirumab in combination with FOLFIRI including irinotecan 150 mg/m2, which is the recommended dose in Japan and is used as initial dose in Japanese clinical practice, was similar to that of the global, phase 3 RAISE study with irinotecan 180 mg/m2. The desirable effect of FOLFIRI plus ramucirumab was observed in patients with wild-type RAS, primary tumors on the left sides(descending, sigmoid, or rectum colons), or who received anti-epidermal growth factor receptor agents, including panitumumab or cetuximab, as previous treatment. Also, the effectiveness of FOLFIRI plus ramucirumab as a late-line treatment was suggested. Several patients were reported to have nephrosis syndrome after starting ramucirumab, but they recovered with discontinuation of ramucirumab and appropriate treatment. No new safety concerns were observed from the literature or the interim report of post-marketing surveillance study.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Japan; Leucovorin; Neoplasm Metastasis; Ramucirumab

Topics: Aged; Aged, 80 and over; Albumin-Bound Paclitaxel; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Comorbidity; Deoxycytidine; Diabetes Mellitus; Diet; Drug Resistance, Neoplasm; Early Detection of Cancer; Fluorouracil; Gemcitabine; Genetic Predisposition to Disease; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Metastasis; Oxaliplatin; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Radiosurgery; Risk Factors; Spain

AMP-activated protein kinase (AMPK) is a key sensor of energy homeostasis and regulates cell metabolism, proliferation and chemotherapy/radiotherapy sensitivities. This study aimed to explore the relationship between the AMPK pathway-related single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with metastatic colorectal cancer (mCRC). We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC and FIRE-3: where patients were treated with FOLFIRI, mFOLFOX6 or FOLFOXIRI combined with bevacizumab or cetuximab as the first-line chemotherapy). The association between AMPK pathway-related SNPs and clinical outcomes was analyzed across the six treatment cohorts, using a meta-analysis approach. Our meta-analysis showed that AMPK pathway had significant associations with progression-free survival (PFS; p < 0.001) and overall survival (OS; p < 0.001), but not with tumor response (TR; p = 0.220): PRKAA1 rs13361707 was significantly associated with favorable PFS (log HR = -0.219, SE = 0.073, p = 0.003), as well as PRKAA1 rs10074991 (log HR = -0.215, SE = 0.073, p = 0.003), and there were suggestive associations of PRKAG1 rs1138908 with unfavorable OS (log HR = 0.170, SE = 0.083, p = 0.041), and of UBE2O rs3803739 with unfavorable PFS (log HR = 0.137, SE = 0.068, p = 0.042) and OS (log HR = 0.210, SE = 0.077, p = 0.006), although these results were not significant after false discovery rate adjustment. AMPK pathway-related SNPs may be predictors for chemotherapy in mCRC. Upon validation, our findings would provide novel insight for selecting treatment strategies.

Topics: AMP-Activated Protein Kinases; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Polymorphism, Single Nucleotide; Prognosis; Progression-Free Survival; Randomized Controlled Trials as Topic; Signal Transduction

Important developments in chemotherapy for metastatic colorectal cancer over the last years are reviewed, with an emphasis on the most recently published data from clinical trials. The systematic review of current literature was conducted involving Pubmed Central

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Vascular Endothelial Growth Factor A

The addition of cetuximab to FOLFIRI or FOLFOX as the first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated systematic meta-analysis was undertaken to determine the efficacy of cetuximab plus FOLFIRI or FOLFOX.Major databases were searched to identify RCTs investigating wild-type KRAS mCRC after the first-line treatment, and treatment with FOLFOX/FORFIRI ± cetuximab was compared. Data on clinical efficacy and safety were pooled and compared by ORs, HRs, and 95% CIs.Five eligible trials with 1464 patients were included in the meta-analysis. Compared to FOLFOX/FORFIRI, cetuximab as the first-line therapy has improved overall survival (OS) (hazard ratio [HR] = 0.82, 95% confidence interval [CI]: 0.72-0.93, P = 0.003), progression-free survival (PFS) (HR = 0.66, 95% CI: 0.56 -0.77, P < 0.00001), and overall response rate (ORR) (odds ratio [OR] = 2.12, 95% CI: 1.70-2.65, P < 0.00001). However, Grade 3/4 AE was increased with the OR of 2.76 (95%CI: 2.01-3.78, P < 0.00001). The most common grade 3/4 toxicity in the wild-type KRAS population was neutropenia and diarrhea. For cetuximab plus FOLFIRI, there was a higher incidence of grade 3 or 4 diarrhea (OR = 1.76, 95% CI: 1.15-2.70, P = 0.01), but there was no significant difference for neutropenia (OR = 1.35, 95% CI: 1.00-1.83, P = 0.05).The addition of cetuximab in mCRC as the first-line treatment is a potential effective approach in the improved outcomes but associated with increased toxicity.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Grading; Neoplasm Metastasis; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras); Survival Analysis

The combination of cetuximab with an oxaliplatin-based chemotherapy is becoming a consolidate standard as first line treatment of metastatic colorectal cancer in RAS wild type patients either in the neoadjuvant setting or in the continuum of care of never resectable disease. Available evidence from clinical trials (not considering regimens containing capecitabine or bolus 5-Fu, as in the COIN and NORDIC study, respectively) has clearly outlined the safety and the efficacy of the combination of FOLFOX and cetuximab. Even the update of the Calgb/Swog 80405 study (with more than 70% of patients treated with FOLFOX) clearly supports the superior activity of FOLFOX+cetuximab in left-sided tumors (70-80% of the real-world population) over chemotherapy + bevacizumab.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

Cytotoxic chemotherapy is the mainstay treatment for metastatic colorectal cancer (mCRC). Fluoropyrimidines, oxaliplatin, and irinotecan are the most active drugs; however, their optimal sequencing has not yet been established. Some evidence has shown that upfront treatment with 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI regimen) can improve outcomes for patients with mCRC.. We performed a systematic search in electronic databases. Studies reporting results from prospective, randomized clinical trials comparing FOLFOXIRI to less aggressive regimens for treatment of mCRC were selected for meta-analysis. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicity were the outcomes of interest. The pooled hazard ratio (HR) and pooled odds ratio (OR) was calculated for the time-to-event endpoints and dichotomous endpoints, respectively.. Four studies were included in the final analysis. The pooled data showed a significant benefit favoring FOLFOXIRI in terms of OS (HR, 0.80; 95% confidence interval [CI], 0.70-0.92), PFS (HR, 0.68; 95% CI, 0.55-0.85), and ORR (OR, 1.9; 95% CI, 1.36-2.67). Toxicity was significantly greater in the FOLFOXIRI arm. Heterogeneity across trials and risk of publication bias were low.. FOLFOXIRI provides superior outcomes for mCRC compared with standard chemotherapy regimens. The toxicity is greater with FOLFOXIRI but manageable. The role of targeted agents combined with FOLFOXIRI is uncertain, and further research is warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Molecular Targeted Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Randomized Controlled Trials as Topic; Survival Rate

Uncertainty exists regarding the comparative effectiveness of triplet chemotherapy (FOLFOXIRI) as backbone first-line chemotherapy for metastatic colorectal cancer (mCRC). We conducted a systematic review and meta-analysis of randomized-controlled trials (RCTs) comparing triplet versus doublet chemotherapy (FOLFOX or FOLFIRI) as first-line therapy in mCRC. Methods and reporting followed PRISMA and SAMPL guidelines. Eight RCTs were included, comprising 1732 patients. In pooled analysis, FOLFOXIRI was associated with improvements in efficacy outcomes, notably with a 25% survival increase (95%CI: 10-37%). FOLFOXIRI was also associated with increased toxicity, with a non-significant 25% increase in the risk of patients experiencing grade ≥3 adverse events (95% CI: -3 to 61%) and with a 1.83 (95% CI: 1.62-2.07) increase in the rate ratio of grade ≥3 adverse events. Moderate quality evidence suggests that first-line FOLFOXIRI provides clinically meaningful efficacy benefits in this setting, at the expense of increased toxicity. Further research is warranted to better characterize safety and to evaluate the most beneficial combination with targeted agents.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

Previous randomized controlled trials (RCTs) and meta-analyses have demonstrated the useless of FOLFIRI alone for previously treated patients with metastatic colorectal cancer (mCRC). The role of FOLFIRI regimen combined with biological therapy is unknown. The purpose of this meta-analysis is to evaluate the efficacy and safety of combining biological therapy with chemotherapy in previously treated patients with mCRC.. MEDLINE, EMBASE, Web of Science, Cochrane library, and ClinicalTrials.gov were searched. Eligible studies were RCTs that evaluated the efficacy and safety of the FOLFIRI regimen with or without biological therapy for previously treated patients with mCRC. The hazard ratio (HR) or risk ratio (RR) with 95% confidence interval was estimated. The Chi-squared and I-squared tests were used to assess the statistical heterogeneity.. The literature search identified 7 RCTs that met the inclusion criteria for the meta-analysis, and 3680 patients with mCRC were included. The meta-analysis showed that combined therapy was associated with a significant improved progression-free survival (PFS) (HR = 0.78, 95% CI = 0.72-0.85, P < .001), overall survival (OS) (HR = 0.84, 95% CI = 0.77-0.92, P < .001), and overall response rate (ORR) (RR = 1.70, 95% CI = 1.25-2.31, P = .001). Sensitivity analysis suggested that combined therapy versus FOLFIRI alone might increase the risk of Grade 3/4 AEs.. The addition of biological therapy to the FOLFIRI regimen improved the PFS, OS, and ORR compared with FOLFIRI alone for previously treated patients with mCRC. Long-term survival outcomes are warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Therapy; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis

To evaluate, from a US payer perspective, the cost-effectiveness of treatment strategies for metastatic colorectal cancer (mCRC), we performed a systematic review of published cost-effectiveness analyses. We identified 14 papers that fulfilled our search criteria and revealed varying levels of value among current treatment strategies. Older agents such as 5-fluorouracil, irinotecan, and oxaliplatin provide high-value treatments. More modern agents targeting the EGFR or VEGF pathways, such as bevacizumab, cetuximab, and panitumumab, do not appear to be cost-effective treatments at their current costs. The analytical methods used within the papers varied widely, and this variation likely plays a significant role in the heterogeneity in incremental cost-effectiveness ratios. The cost-effectiveness of current treatment strategies for mCRC is highly variable. Drugs recently approved by the US Food and Drug Administration for mCRC are not cost-effective, and this is primarily driven by high drug costs.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Costs; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Quality-Adjusted Life Years; Treatment Outcome; United States

The management of metastatic colorectal cancer substantially improved over the last 10 years and median overall survival of patients might exceed 30 months. The selection of an effective first-line treatment represents a crucial point in order to achieve good outcome results. In the last years, the intensive FOLFOXIRI regimen in combination with bevacizumab became a new standard option in this setting. In the present review we summarized the main steps of FOLFOXIRI regimen development from the first pilot study to the recent findings with biological agents, with a specific focus on practical aspects, such as patient's selection, adverse event management, treatment schedules and post-progression strategies. Possible predictive markers, open issues and ongoing clinical trials have been also deeply described.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Fluorouracil; Humans; Leucovorin; Maintenance Chemotherapy; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds

This meta-analysis aims to evaluate chemotherapy with XELOX (capecitabine plus oxaliplatin) versus FOLFOX (fluorouracil plus oxaliplatin) as a treatment for metastatic colorectal cancer (mCRC) in terms of efficacy and safety. Only randomized controlled trials (RCTs) comparing XELOX versus FOLFOX were included. A total of 4,363 patients from eight RCTs were available for analysis. Pooled analysis revealed that there were no statistical differences between both arms in OS, and ORR. XELOX arm had a higher incidence of thrombocytopenia, hand-foot syndrome, and diarrhea, whereas neutropenia had a higher incidence in the FOLFOX group. For mCRC, the effect of XELOX is similar to FOLFOX.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chi-Square Distribution; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Odds Ratio; Organoplatinum Compounds; Oxaloacetates; Risk Factors; Survival Analysis; Time Factors; Treatment Outcome

Colorectal cancer is one of the most frequent solid tumors in the western world, with low survival rates in patients with metastatic disease. Doublet chemotherapy regimens such as FOLFOX or FOLFIRI are the mainstay of standard first-line chemotherapy in the metastatic setting. The conventional treatment as a first-line approach is continuous application until progression or intolerable toxicities. However, only one third of patients are treated until progression mainly due to the side effects of chemotherapy. Notably, oxaliplatin-containing regimens such as FOLFOX/CapOx or FOLFOXIRI are associated with oxaliplatin-induced neuropathy, which is the main reason for treatment discontinuation or treatment de-escalation. On this basis, recent studies have investigated the clinical benefits of bevacizumab-based intermittent and continuous treatment regimens in the metastatic colorectal setting, together with various strategies to optimize maintenance therapy including regimens with targeted therapies, such as cetuximab, ziv-aflibercept and regorafenib. Recent studies have also investigated when maintenance therapy should be initiated as well individualizing treatment based on patient, tumor and treatment characteristics, as well as molecular biomarkers. This article reviews the current evidence for the clinical benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer, and also evaluates the effect of RAS and BRAF mutational status on maintenance strategies.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Genes, ras; Humans; Leucovorin; Maintenance Chemotherapy; Mutation; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pharmacokinetics; Proto-Oncogene Proteins B-raf

Recent studies have paid much attention on the safety of bevacizumab as adjuvant chemotherapy for metastatic colorectal cancer. The aim of this meta-analysis was to study the efficacy and safety of bevacizumab in combination with irinotecan, bolus followed by infusional 5-fluorouracil, and leucovorin (FOLFIRI) and, irinotecan, bolus fluorouracil, leucovorin (IFL) for patients with metastatic colorectal cancer (mCRC).An electronic search of related trials was conducted from PubMed, EMBASE, Cochrane Library databases. Risk ratio (RRs) and its 95% confidence intervals (95% CIs) were calculated by using either DerSimonian-Laird method or Mantel-Haenszel method according to the heterogeneity of included articles. The risk of mortality, therapeutic efficacy, and adverse effect were meta-analyzed.In total, 6 RCTs including 2165 participants (1109 in the treatment group, 1056 in the control group) were included in this meta-analysis. Compared with FOLFIRI-panitumumab/cetuximab, the bevacizumab addition significantly reduced the complete response (CR) rate (RR [95%CI] = 0.31[0.11, 0.89], P = 0.03) and the risk of grade 3/4 adverse event (RR [95%CI] = 0.89[0.80, 0.98], P = 0.01). Compared with FOLFIRI and IFL alone, the addition of bevacizumb significantly increased the partial response (PR) and objective response (OR) rates. Compared with IFL alone, the addition of bevacizumb significantly reduced the mortality risk of PFS (RR [95%CI] = 0.53[0.42, 0.66], P < 0.00001) and OS (RR[95%CI] = 0.70[0.60, 0.82], P < 0.00001), but increased the risk of adverse events (RR[95%CI] = 1.14[1.06, 1.21], P = 0.0002).Combination chemotherapy of bevacizumab plus FOLFIRI or IFL had a relative high efficacy and acceptable safety for treatment of mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Treatment Outcome

The relative efficacy and safety of first-line metastatic colorectal cancer (mCRC) treatment regimens, capecitabine with irinotecan (CAPIRI) and 5-fluorouracil/leucovorin plus irinotecan (FOLFIRI), are not well defined. We identified and subsequently examined seven independent, randomized controlled clinical trials, performing a meta-analysis to compare these two treatment regimens. Using Medline, EMBASE, Cochrane Library (CENTRAL), and the American Society of Clinical Oncology Annual Meeting to search available literature until February 2014, we identified seven studies comparing safety and efficacy of CAPIRI and FOLFIRI in mCRC patients. These studies were pooled and evaluated for rates of progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and diarrhea. CAPIRI and FOLFIRI demonstrated similar efficacy outcomes, though CAPIRI was associated with a higher incidence of diarrhea. CAPIRI and FOLFIRI are equally effective options for first-line treatment of mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Publication Bias

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of aflibercept (Sanofi) to submit clinical and cost-effectiveness evidence for aflibercept in combination with irinotecan and fluorouracil-based therapy [irinotecan/5-fluorouracil/folinic acid (FOLFIRI)] for the treatment of metastatic colorectal cancer which has progressed following prior oxaliplatin-based chemotherapy, as part of the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA307 issued in March 2014. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The clinical effectiveness data were derived from one good-quality double-blind randomised controlled trial (RCT), the VELOUR trial, which compared aflibercept plus FOLFIRI with placebo plus FOLFIRI. This RCT found a small but statistically significant increase in overall survival (OS); the difference in median OS was 1.44 months (13.5 months in the aflibercept group and 12.06 months in the placebo group). There was also a statistically significant increase in progression-free survival (PFS) with aflibercept; the difference in median PFS was 2.23 months (6.9 months in the aflibercept group and 4.67 months in the placebo group). However, grade 3-4 adverse events were more frequent in the aflibercept group than the placebo group: 83.5% compared with 62.5%. Treatment-emergent adverse events led to permanent discontinuation of treatment in 26.8% of patients in the aflibercept group and 12.1% of patients in the placebo group. The manufacturer's submission included an estimation of mean OS benefit based on extrapolation of the data, which was considerably longer than the median OS benefit reported (4.7 vs. 1.44 months). The ERG considered this to be an over estimate. The base-case incremental cost-effectiveness ratio (ICER) for the overall population was reported by the manufacturer to be £36,294 per quality-adjusted life-year (QALY). After correcting the model programming and updating the model to include the ERG's preferred parameter estimates, the ICER from the ERG's alternative base case was £54,368 per QA

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Cost-Benefit Analysis; Disease Progression; Disease-Free Survival; Fluorouracil; Health Care Costs; Humans; Kaplan-Meier Estimate; Leucovorin; Models, Economic; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

Despite a slight decrease in mortality rates, recent advances in screening methods, diagnosis and overall improved therapeutic options, colorectal cancer (CRC) remains among the leading causes of cancer-related death worldwide. The major cause is the mortality related to metastatic status of CRC. Increasing clinical evidence derived from randomized trials strongly suggests that the efficacy of standard cytotoxic agents, including various combinations of 5-fluoouracil (5-FU)/leucovorin (LV), capecitabine, irinotecan and oxaliplatin, may be significantly augmented with concomitant administration of molecular agents targeting the vascular endothelial growth factor (VEGF) signaling pathways, such as bevacizumab. Herein, we critically discuss the current data on the efficacy and safety profile of bevacizumab in combination with fluoropyrimidine-based chemotherapy for first-line and maintenance treatment of metastatic CRC and briefly comment on existing controversies and future perspectives.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Molecular Targeted Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A

Colorectal cancer is a lethal disease if not discovered early. Even though appropriate screening and preventive strategies are in place in many countries, a significant number of patients are still diagnosed at late stages of the disease. The management of metastatic colorectal cancer remains a significant clinical challenge to oncologists worldwide. While cytotoxic regimens constitute the main treatment of choice in this patient population, addition of the five biologics (bevacizumab, cetuximab, aflibercept, panitumumab and regorafenib) to these regimens has improved clinical outcomes. The most commonly used cytotoxic regimens include doublet combinations (FOLFOX/XELOX or FOLFIRI). Many clinical trials have been published and others are underway to compare the biologic agents with one another in order to prove the superiority of one regimen over another. Metastatic colorectal cancer patients have many treatment options; however, the optimal use and sequence of targeted agents remain to be determined. This review entails concise and updated clinical data on the management of metastatic colorectal cancer. The aim of the review is to determine where to fit the five biologic targets into the treatment algorithm of metastatic colorectal cancer patients and to derive treatment sequences that would achieve best clinical outcome based on the current available data.

Topics: Algorithms; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Clinical Trials as Topic; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Phenylurea Compounds; Pyridines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

The treatment of metastatic colorectal cancer (mCRC) has evolved considerably in the last decade, currently allowing most mCRC patients to live more than two years. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor play an important role in the current treatment of these patients. However, only antibodies directed against EGFR have a predictive marker of response, which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC. The CRYSTAL study showed that adding cetuximab to FOLFIRI (regimen of irinotecan, infusional fluorouracil and leucovorin) significantly improved results in the first-line treatment of KRAS wild-type mCRC. However, results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory. On the other hand, recent advances in the management of colorectal liver metastases have improved survival in these patients. Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients. In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Cetuximab; Clinical Trials as Topic; Colorectal Neoplasms; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Ligands; Liver Neoplasms; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome; Vascular Endothelial Growth Factor A

We report a case of recurrent colon cancer successfully treated by mFOLFOX6 and FOLFIRI, and maintaining a complete response(CR)over the long-term. A 60-year-old woman complained of abdominal discomfort 18 months after surgery for advanced descending colon cancer(tub2, pT3, pN2, cM0, fStage IIIb). A pelvic mass was demonstrated by abdominal computed tomography(CT)scan, and relapse of the cancer was suspected. Positron emission tomography-CT fusion image revealed metastases at Douglas' pouch, liver, right ovary and right inguinal lymph nodes. Systemic chemotherapy followed by mFOLFOX6 regimen was started. After 8 courses of mFOLFOX6, severe neuralgic side effects forced us to change the regimen to FOLFIRI. After completion of 4 courses of FOLFIRI, CR was proved by CT scan. Chemotherapy was stopped after an additional 4 courses of FOLFIRI. CR has been maintained for 4 years and 4 months after confirmation of CR. There were 18 cases reported in the literature that had CR by FOLFOX and/or FOLFIRI. Among those reports, our case was considered to have kept CR for the longest duration of time.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Recurrence; Time Factors

The patient was a 54-year-old man who had undergone resection of the sigmoid colon for unresectable sigmoid colon cancer with multiple liver( H1), lymph node, and lung metastases at the previous hospital. Chemotherapy with 5-fuorouracil, Leucovorin, and oxaliplatin (mFOLFOX6) plus bevacizumab was initiated after surgery. The outcome was partial response. The patient was introduced to our hospital because he had relocated. Based on the findings of the patient's computed tomography( CT) and positron emission tomography( PET)-CT scans, we decided to perform radical resection. We performed partial hepatectomy( S7 and S8) and pancreatoduodenectomy for metastases to the hepatoduodenal ligament lymph node. After confirming that there was no recurrence, he underwent right partial pneumonectomy. Currently, the patient shows no signs of recurrence. The therapy for colon cancer should include aggressive radical surgery to control metastasis.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Sigmoid Neoplasms

The pharmacogenomics field is crucial for optimizing the selection of which chemotherapy regimen to use according to the patient's genomic profile. Indeed, the individual's inherited genome accounts for a large proportion of the variation in his or her response to chemotherapeutic agents both in terms of efficiency and toxicity. Patients with metastatic disease are more likely to receive different lines of chemotherapy with variable efficacy and experience some related complications. It is therefore critical to tailor the best therapeutic arsenal to improve the efficacy and avoid as much as possible related complications that are susceptible to interrupt the treatment. The pharmacogenomics approach investigates for each drug the implicated metabolic pathway and the potential personal variations in gene function. The aim of this review is to present a clear overview of the most accurate polymorphisms that have been identified as related to drug response in patients with mCRC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pharmacogenetics; Polymorphism, Genetic

Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer.. A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival.. Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis.. Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chronotherapy; Circadian Clocks; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Sex Factors; Survival Rate; Treatment Outcome

Cetuximab (Erbitux(®)) is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR). In the USA, the approval of cetuximab has been recently expanded to include the first-line treatment of patients with KRAS mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer (mCRC) when used in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin [folinic acid]). The addition of cetuximab to first-line treatment with FOLFIRI improved progression-free survival, overall survival, and objective response rates relative to treatment with FOLFIRI alone in patients with EGFR-expressing mCRC with KRAS wild-type tumors. Therefore, cetuximab plus FOLFIRI is a useful biomarker-directed option in the first-line treatment of this patient population.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; ErbB Receptors; Fluorouracil; Gene Expression Regulation, Neoplastic; Guidelines as Topic; Humans; Leucovorin; Mutation; Neoplasm Metastasis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins

To investigate oxaliplatin-induced severe anaphylactic reactions (SAR) in metastatic colorectal cancer in a retrospective case series analysis and to conduct a systemic literature review.. During a 6-year period from 2006 to 2011 at Kaohsiung Veterans General Hospital, a total of 412 patients exposed to oxaliplatin-related chemotherapy were retrospectively reviewed. Relevant English-language studies regarding life-threatening SAR following oxaliplatin were also reviewed in MEDLINE® and PubMed® search.. Eight patients (1.9%, 8 of 412 cases) were identified. Seven patients were successful resuscitated without any sequelae and one patient expired. We changed the chemotherapy regimen in five patients and rechallenged oxaliplatin use in patient 3. Twenty-three relevant English-language studies with 66 patients were reported. Patients received a median of 10 cycles of oxaliplatin (range, 2 to 29). Most common symptoms were respiratory distress (60%), fever (55%), and hypotension (54%). Three fatal events were reported (4.5%). Eleven patients (16%) of the 66 cases were rechallenged by oxaliplatin.. SAR must be considered in patients receiving oxaliplatin-related chemotherapy, especially in heavily pretreated patients. Further studies on the mechanism, predictors, preventive methods and management of oxaliplatin-related SAR are recommended.

Topics: Adult; Aged; Anaphylaxis; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Severity of Illness Index

Because mFOLFOX6 has few contraindications, it is useful for poor performance status(PS)cases. However, in Japan, there are some reports that the dose is reduced easily. We retrospectively examined the safety/usefulness of the full dose mFOLFOX6(first-line)for advanced colon cancer patients with poor PS. Four of five cases had improved PS. The response rate was 60%. Grade 3/4 adverse events were infection, leukopenia, and neutropenia. Treatment-related deaths within 60 days of starting treatment were absent. Full-dose mFOLFOX6 for poor PS may be beneficial. However, we must consider the increased risk of adverse events.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

The simultaneous administration of irinotecan, 5-fluorouracil, folinic acid and oxaliplatin (FOLFOXIRI) has been compared with standard 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) in randomized trials in metastatic colorectal cancer patients. A superior efficacy of FOLFOXIRI has been reported by some authors, but others have failed to show any differences and do not recommend its use because of greater cost and toxicity. We performed a systematic review of the literature to analyse efficacy and toxicity of FOLFOXIRI.. Odds ratios (OR) with 95% confidence intervals (CI) were used to analyse dichotomous variables. Hazard ratios (HR) for progression and death were combined with an inverse variance method based on logarithmic conversion. A fixed-effect model and Mantel-Haenszel's method were used. Heterogeneity was tested with Cochrane's Q test and I(2) test.. A significant increase in response rate (OR 2.04; P < 0.01) was associated with treatment by FOLFOXIRI and a benefit was also shown by the HR for progression (HR 0.72; P < 0.01) and death (HR 0.71; P < 0.01). Analysis for toxicity found a significant increase associated with FOLFOXIRI except for anaemia, fatigue and febrile neutropenia.. FOLFOXIRI confers significant benefit in progression-free survival, survival, response and R0 resection rates but is more toxic compared with FOLFIRI.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

Metastatic colorectal cancer (MCRC) remains a significant public health concern. The objectives of present study are to investigate the efficacy and safety profile of capecitabine-based chemotherapy in the treatment of MCRC.. We performed a computerized search using combinations of the following keywords: "metastatic colorectal cancer," "Xeloda," "chemotherapy," "capecitabine," or "5-fluorouracil.". Treatment with capecitabine chemotherapy was associated with a significantly prolonged progression-free survival (WMD = 1.24; 95% CI, 0.04-2.44; P = 0.04), whereas overall survival was not statistically significant (WMD [random] = 0.29; P = 0.75). Patients in both capecitabine and 5-fluorouracil groups had equal 1-, 2-, and 3-year survival (OR = 0.82, 95% CI: 0.59-1.12, P = 0.21; OR = 0.84, 95% CI: 0.61-1.15, P = 0.27; OR = 1.26, 95% CI: 0.78-2.05, P = 0.34; respectively). The analysis also demonstrates that the response rate of capecitabine-based chemotherapy was comparable to 5-fluorouracil-based chemotherapy (OR = 1.02, 95% CI, 0.90-1.14; P = 0.80). When comparing single-agent capecitabine against 5-fluorouracil/leucovorin, our results showed an overall OR of 1.56 (95% CI, 1.16-2.09) in favor of the capecitabine arm. When toxicity was evaluated, a statistically significant benefit with capecitabine-based therapy was seen, especially for grade 3/4 neutropenia (OR, 0.80; 95% CI, 0.71-0.91; P = 0.00005).. Capecitabine-based chemotherapy demonstrated a significantly superior progression-free survival, equivalent overall survival, and comparable response rate with 5-fluorouracil-based chemotherapy. These observations support the use of capecitabine-based chemotherapy in the treatment of MCRC as a first-line or as a neoadjuvant modality.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

Capecitabine is an oral fluoropyrimidine that is shown to have similar efficacy to 5-fluorouracil (5-FU) when used both alone and in combination with oxaliplatin in the treatment of colorectal cancer (CRC). Capecitabine and irinotecan combinations (XELIRI) have been developed for the treatment of this disease but randomized comparisons with standard infusional 5-FU and irinotecan (FOLFIRI) showed conflicting results.. We searched the literature for randomized controlled trials comparing XELIRI to FOLFIRI for the treatment of metastatic colorectal cancer. Odds ratios with 95% confidence intervals were used to analyze dichotomous variables. Hazard ratios for progression and death were combined with an inverse variance method based on logarithmic conversion. The fixed-effect model and Mantel-Haenszel method were used. Heterogeneity was investigated with the Q-test and I2. Sensitivity analyses were performed.. Only 3 studies were identified, involving a total of 450 patients. XELIRI was associated with significantly shorter progression-free survival (PFS) and increased grade 3/4 gastrointestinal toxicities such as nausea, vomiting, and diarrhea. Severe neutropenia, however, was significantly more frequent with FOLFIRI. No differences in responses and febrile neutropenia events were observed.. Our analysis suggest that the 2 regimens are not equivalent. XELIRI remains an option for the first-line treatment of metastatic CRC but FOLFIRI should be preferred as it confers more benefits in terms of PFS and induces fewer GI toxicities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Treatment Outcome

Without treatment, patients with inoperable or metastatic colorectal cancer have a median life expectancy of about 8 months. The following article is an update of our 2005 review of chemotherapy regimens used in metastatic colorectal cancer, based on the standard Prescrire methodology. In 2005, the de Gramont protocol, based on fluorouracil (always combined with folinic acid) plus either oxaliplatin (Folfox protocol) or irinotecan (Folfiri protocol), was the standard first-line chemotherapy in this setting. Four trials comparing monotherapy versus combination therapy in previously untreated patients showed that initial fluorouracil (or fluorouracil precursor) monotherapy, followed by the Folfox or Folfiri protocol in case of failure, was not associated with shorter overall survival. Two trials compared first-line treatment with the Folfiri regimen versus the Folfoxiri regimen (fluorouracil + oxaliplatin + irinotecan). One of these studies showed an increase in median survival with the Folfoxiri protocol (24 versus 17 months), but at a cost of greater neurotoxicity. The only tangible advantage of capecitabine and tegafur, two oral fluorouracil precursors, is their convenience of use. Pemetrexed was less effective and more toxic than the Folfiri protocol in one trial. Bevacizumab and panitumumab have yielded disappointing results in previously untreated patients. Neither of these monoclonal antibodies has yet been shown to improve overall survival. Three trials have assessed the addition of cetuximab to combinations consisting of fluorouracil or capecitabine plus oxaliplatin or irinotecan. In two of these trials, the median survival time of patients whose tumours carried the wild-type KRAS gene was about 3 months longer in the cetuximab arms, although the increase was statistically significant in only one trial. Cetuximab had no impact on survival time in the third trial. In two trials, an anti-EGFR antibody (panitumumab or cetuximab) reduced median survival when added to bevacizumab in previously untreated patients. When progression occurs after treatment with the Folfiri protocol (or equivalent), a combination of the Folfox protocol and bevacizumab seems to increase median survival time by about 2 months versus Folfox alone, but it is also more toxic. In patients who progress after receiving the fluorouracil + oxaliplatin combination (Folfox) or the fluorouracil+ irinotecan combination (Folfiri), neither panitumumab nor cetuximab has been shown to provide

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

Radioembolization with yttrium-90 microspheres ((90)Y-RE), either glass- or resin-based, is increasingly applied in patients with unresectable liver malignancies. Clinical results are promising but overall response and survival are not yet known. Therefore a meta-analysis on tumor response and survival in patients who underwent (90)Y-RE was conducted. Based on an extensive literature search, six groups were formed. Determinants were cancer type, microsphere type, chemotherapy protocol used, and stage (deployment in first-line or as salvage therapy). For colorectal liver metastases (mCRC), in a salvage setting, response was 79% for (90)Y-RE combined with 5-fluorouracil/leucovorin (5-FU/LV), and 79% when combined with 5-FU/LV/oxaliplatin or 5-FU/LV/irinotecan, and in a first-line setting 91% and 91%, respectively. For hepatocellular carcinoma (HCC), response was 89% for resin microspheres and 78% for glass microspheres. No statistical method is available to assess median survival based on data presented in the literature. In mCRC, (90)Y-RE delivers high response rates, especially if used neoadjuvant to chemotherapy. In HCC, (90)Y-RE with resin microspheres is significantly more effective than (90)Y-RE with glass microspheres. The impact on survival will become known only when the results of phase III studies are published.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoembolization, Therapeutic; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Glass; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Microspheres; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome; Yttrium Radioisotopes

Surgery is the only curative option for patients with liver metastases of colorectal cancer, but few patients present with resectable hepatic lesions. Chemotherapy is increasingly used to downstage initially unresectable disease and allow for potentially curative surgery. Standard chemotherapy regimens convert 10%-20% of cases to resectable disease in unselected populations and 30%-40% of those with disease confined to the liver. One strategy to further increase the number of candidates eligible for surgery is the addition of active targeted agents such as cetuximab and bevacizumab to standard chemotherapy. Data from a phase III trial indicate that cetuximab increases the number of patients eligible for secondary hepatic resection, as well as the rate of complete resection when combined with first-line treatment with the FOLFIRI regimen. The safety profiles of preoperative cetuximab or bevacizumab have not been thoroughly assessed, but preliminary evidence indicates that these agents do not increase surgical mortality or exacerbate chemotherapy-related hepatotoxicity, such as steatosis (5-fluorouracil), steatohepatitis (irinotecan), and sinusoidal obstruction (oxaliplatin). Secondary resection is a valid treatment goal for certain patients with initially unresectable liver metastases and an important end point for future clinical trials.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Treatment Outcome

Colorectal cancers are rare in developing countries, but are the second most frequent malignancy in the affluent world. Data on colorectal cancer in HIV-positive patients are limited. Up to now, there are no published data on treatment patterns, response to therapy, or survival in this setting. Oxaliplatin is an antineoplastic agent currently indicated, concomitantly to fluorouracil and leucovorin, for the treatment of advanced colorectal cancer. The FOLFOX-4 regimen (oxaliplatin 85 mg/m(2) as a two-hour infusion on day 1; leucovorin 200 mg/m(2) as a two-hour infusion on days 1 and 2, fluorouracil as a bolus infusion on days 1 and 2, followed by a fluorouracil 22-hour infusion 600 mg/m(2) for two consecutive days every two weeks), with concomitant highly active antiretroviral therapy (HAART) is feasible and active, while the HIV infection is not a limiting factor for its use. Moreover, the concomitant use of HAART does not seem to increase the toxicity of the FOLFOX-4 regimen.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Colorectal Neoplasms; Female; Fluorouracil; HIV Infections; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

Continuous-infusion 5-fluorouracil (5-FU)/leucovorin (LV) and oxaliplatin is a frequently used regimen in metastatic colorectal cancer. Continuous-infusion 5-FU imposes constraints on patients and institutions. Oral fluoropyrimidines that mimic continuous-infusion 5-FU are now available and can be combined with oxaliplatin. In addition, it has been shown in small randomized trials that oral fluoropyrimidines are preferred by patients. Several randomized trials have compared continuous-infusion 5-FU/oxaliplatin with the oral fluoropyrimidine capecitabine plus oxaliplatin. In all of these trials, noninferiority was demonstrated for the use of oral fluoropyrimidines on the predefined endpoints such as progression-free survival, overall survival, or response rate. In all trials, however, the hazard ratios were always in favor of the use of continuous-infusion 5-FU/LV even though noninferiority was demonstrated. This could question the need to use oral fluoropyrimidines instead of continuous-infusion 5-FU. Patient preference, quality of life, and cost of treatment could also be considered in this setting, wherein most of the patients are not in a curative situation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis

The introduction of targeted therapies in the treatment of metastatic colorectal cancer (MCRC) has resulted in significant improvements in efficacy outcomes. Both vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors have proven to be valid and valuable agents in the management of MCRC. This review will focus on the role of the anti-VEGF monoclonal antibody, bevacizumab, and the anti-EGFR monoclonal antibodies, cetuximab and panitumumab, in MCRC. Special focus will be placed on clinical evidence supporting the use of these agents in various lines of treatment, and on KRAS as a marker of response in relationship to anti-EGFR inhibitors.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Panitumumab; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A

Advances in the medical treatment of colorectal cancer patients have resulted in considerable improvements through the introduction of new cytotoxic drugs. The significant progress in molecular and tumour biology has produced a great number of targeted, tumour-specific, monoclonal antibodies that are now in various stages of clinical development. Two of these antibodies, cetuximab (Erbitux) und bevacizumab (Avastin), directed against the epidermal growth factor receptor (EGFR) and the vascular epithelial growth factor (VEGF), respectively, have recently been approved for use in metastatic colorectal cancer. The combination of well-known and newly developed cytotoxic agents with monoclonal antibodies makes the medical treatment of colorectal cancer patients considerably more complex, but also provides additional therapeutic strategies for patients in advanced stages of disease.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bevacizumab; Camptothecin; Cetuximab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Drug Therapy, Combination; Epidermal Growth Factor; ErbB Receptors; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Panitumumab; Phthalazines; Pyridines; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A; Vitamin B Complex

The liver is a frequent site of metastatic disease for colorectal cancer patients. Approximately 15% of patients have liver metastases at diagnosis and another 50% develop metastatic disease to the liver over the course of their disease. Advances in systemic chemotherapy and surgical techniques for hepatic resection have led to longer survival times for these patients. There is no doubt that unresectable patients benefit from systemic chemotherapy. For patients who have resectable disease, the timing of chemotherapy is still not clear. This review addresses the pros and cons of presurgical chemotherapy. The benefits of preoperative chemotherapy include decreasing tumor size, controlling micrometastatic disease, assessing activity of chemotherapy, improving chemotherapy tolerance, and perhaps allowing some prediction of the success of liver resection. The risks for presurgical chemotherapy include liver toxicity, the risk for progression or growth of new sites, secondary splenomegaly, selection of resistant clones, and the possibility of leaving behind active tumor that is no longer seen because of a complete radiographic response. The challenge for the future is to develop a multidisciplinary team approach that can design the best treatment plan for patients with liver metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Patient Selection; Preoperative Care; Survival Analysis; Treatment Outcome

Surgery alone is no longer appropriate to the treatment of T3-T4 resecable rectal cancer. Preoperative chemoradiotherapy has recently been approved as the new standard treatment. This approach improves local control with local failure rate raranging now around 6-8%. However, it does not impact on overall survival. It becomes urgent to develop new concepts and a basic research in the understanding of the biological mechanisms that may explain the resistance of the micrometastatic process.

Topics: Antimetabolites, Antineoplastic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Preoperative Care; Prognosis; Radiotherapy Dosage; Randomized Controlled Trials as Topic; Rectal Neoplasms; Rectum; Tomography, X-Ray Computed; Vitamin B Complex

Bevacizumab is a humanised monoclonal antibody, which has demonstrated significant activity in metastatic colorectal cancer. The aim of this study is to estimate the cost-effectiveness of adding bevacizumab to chemotherapy for patients with untreated metastatic colorectal cancer.. A decision-analytic model was developed to estimate the lifetime costs and benefits of adding bevacizumab to irinotecan plus FU/LV (IFL) or 5-FU/LV alone. Effectiveness outcomes, health utilities and resource use data were derived from recent bevacizumab RCTs and from the literature.. Adding bevacizumab to IFL costs approximately pound62,857 per QALY gained. Adding bevacizumab to 5-FU/LV costs approximately pound88,436 per QALY gained. The acquisition cost of bevacizumab is a key determinant of its cost-effectiveness. The probability that bevacizumab has a cost-effectiveness ratio that is better than pound30,000 per QALY gained is close to zero.. Given high acquisition costs in relation to clinical benefits, bevacizumab is unlikely to represent a cost-effective use of NHS resources.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Cost-Benefit Analysis; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Analysis

Topics: Age Factors; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Vascular Endothelial Growth Factor A

The management of patients with metastatic colorectal cancer (CRC) has changed dramatically over the last five years, with increasing chances of prolonged survival. The development of new drugs has contributed to the better outcome of patients with metastatic colorectal cancer. Until the mid-1990s the only available drug, with limited activity in metastatic CRC, was 5-fluorouracil (5-FU). The development of the cytotoxic agents irinotecan, oxaliplatin and capecitabine and of the monoclonal antibodies against the vascular endothelial growth factor (VEGF) bevacizumab and against the epidermal growth factor receptor (EGFR) cetuximab and panitumumab have clearly increased the therapeutic options and have improved the outcome for patients with metastatic colorectal cancer. However, their introduction also raises many new questions and challenges.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cell Death; Cell Survival; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Tegafur; Treatment Outcome; Uracil; Vascular Endothelial Growth Factor A

For the past several decades, the therapy for metastatic colorectal cancer had modest benefits because of the limited therapeutic options. Bolus 5-fluorouracil (5FU) and leucovorin (LV) were the standard of care in the United States until 2002, with a response rate of 25% and a median survival of 10 to 12 months. However, with the advent of new agents, namely oxaliplatin and irinotecan, there has been a dramatic change in the way we treat metastatic colorectal cancer. Based on many well-conducted large randomized trials, we have evidence that combination chemotherapy incorporating oxaliplatin or irinotecan with infusional 5FU/LV is superior to 5FU/LV, with doubling of overall survival (OS) to approximately 20 months. There remains some uncertainty as to the best first-line regimen. This might be irrelevant because studies have shown that OS is dependent on exposure to all the active agents, regardless of the time period of exposure. Bevacizumab, which uses anti-angiogenic strategies, has improved disease-free survival (DFS) and OS when combined with standard chemotherapy and is a vital component of metastatic colorectal cancer therapy. However, there are no data supporting its use past progression. Cetuximab, an epithelial growth factor receptor inhibitor, is mainly used in irinotecan-refractory patients. In spite of all these advances, 5-year OS rates continue to be limited. Patients with curative resection of metastatic disease seem to have longer DFS and better 5-year OS rates. This should be a potential goal for responding patients with upfront unresectable, organ-limited disease.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

It is a common belief that older patients and those with less-than-ideal performance status do not tolerate chemotherapy as well as other patients. In fact, many otherwise-healthy older patients with metastatic colorectal cancer are not treated with chemotherapy. There is strong evidence that the addition of bevacizumab to the combination of irinotecan, 5-fluorouracil, and leucovorin or to 5-fluorouracil and leucovorin has substantial clinical benefits in patients 65 years of age or older and in those with Eastern Cooperative Oncology Group performance status 1 or 2. The treatment is generally well tolerated, without apparent negative effects on quality of life. However, the toxicity profile differs slightly, and the risk of arterial thrombotic events with bevacizumab-containing regimens, while relatively low, is higher in older patients than in younger patients. Clinicians should weigh the potential survival benefits against the risk of adverse events when choosing therapy for older patients with metastatic colorectal cancer and for those with poorer performance status.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Quality of Life; Thrombosis

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, was approved in 2004 for use in combination with intravenous 5-fluorouracil-based chemotherapy for the treatment of metastatic colorectal cancer. Bevacizumab is the first approved agent that targets tumor angiogenesis. The pivotal phase III trial showed significantly greater overall and progression-free survival with the addition of bevacizumab to irinotecan, 5-fluorouracil, and leucovorin. These outcomes were observed irrespective of patients' pretreatment characteristics (age >/=65 years, >/=1 site of metastasis, or location of primary tumor). Furthermore, there was a significant survival benefit regardless of pretreatment biomarkers, including plasma vascular endothelial growth factor level, tumor thrombospondin and p53 expression, and mutational status in k-ras, b-raf, and p53. Analysis of data in responders and nonresponders showed a response-independent survival benefit, indicating that even those in whom there was not an objective tumor response by standard criteria benefited from the addition of bevacizumab. Preliminary data on the addition of bevacizumab to oxaliplatin- and capecitabine-based regimens for the first-line treatment of metastatic colorectal cancer show that these regimens are well tolerated, with consistent increases in objective response rates, time to progression, and overall survival. The survival advantages in patients with metastatic colorectal cancer with the addition of bevacizumab to chemotherapy support the use of this agent in first-line treatment.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

Since the introduction of combined systemic chemotherapy with 5-folinic-acid (FA) and/or oxaliplatin or irinotecan, the median survival in patients with advanced colorectal cancer has increased to more than 20 months. Novel agents in so-called targeted therapies such as monoclonal antibodies will further increase these excellent survival data in the near future.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prodrugs

Irinotecan is a cornerstone drug in the management of metastatic colorectal cancer, as demonstrated by several randomized studies proving a survival benefit for the first time. In the adjuvant setting, FOLFOX (infusional 5-fluorouracil [5-FU]/leucovorin [LV] in combination with oxaliplatin) has improved 3-year disease-free survival in stage II/III colorectal cancer in the MOSAIC trial. Because 5-FU/LV-based combination therapy with oxaliplatin or irinotecan has similar efficacy in metastatic disease in the first-line setting, the impact of irinotecan in the adjuvant setting deserves further randomized clinical trials. Six such trials are ongoing or have already been closed to accrual, the results of which will be reported shortly. Five of these trials presently accruing patients or already closed combine irinotecan with an infusional regimen of 5-FU, based on a better tolerance and efficacy profile established in the metastatic setting according to clinical trials conducted principally in Europe. The results of 2 main randomized trials in the adjuvant therapy of stage III colon cancer will be presented at the 41st Annual Meeting of the American Society of Clinical Oncology in 2005 and are eagerly awaited. These results should provide important new insights as to how to manage stage II/III colon cancer.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

Colorectal cancer is the most commonly diagnosed cancer in the EU. Various randomised studies have shown a survival benefit with chemotherapy in the adjuvant setting. Adjuvant chemotherapy with 5-fluorouracil/folinic acid (5FU/FA) for 6 months after curatively resected node-positive colon cancer has become the standard practice. However, controversy still exists regarding the optimal regimen and whether to treat node-negative patients. The latest QUASAR trial results seem to strengthen the argument in favour of adjuvant treatment of Dukes B cancer. Patients with Dukes B tumours and any adverse prognostic indicator should be given the benefit of adjuvant therapy. A number of novel agents (oxaliplatin, irinotecan) showing activity in advanced disease are currently being evaluated in the adjuvant setting. A patient with metastatic colorectal cancer should today be expected to have a median survival of 18-20 months compared to that of 11-14 months only a few years ago. 5FU/FA has been the mainstay of therapy for metastatic colorectal cancer for over 40 years and confers a survival benefit over supportive care. The response rate of 5FU is improved by modulation with FA or by continuous infusional regimens (currently the best expected response rate is around 20-25%). As per the recent National Institute for Clinical Excellence guidelines, the oral agents capecitabine or tegafur with uracil (in combination with FA) can be used as first-line treatment in metastatic colorectal cancer and, although their response rate has not been directly compared to infusional 5FU, survival is unlikely to be inferior. Newer chemotherapeutic agents like irinotecan and oxaliplatin are now entering regular usage due to improved response rates (around 50% in 5FU/FA-containing doublets) and survival. Irinotecan monotherapy is second-line treatment approved by the National Institute for Clinical Excellence, although sequential infusional 5FU/FA irinotecan to infusional 5FU/FA oxaliplatin may convey the best survival with the least side effects. The position of combination chemotherapy before (to downstage) or after metastasectomy (usually from the liver) is still a topic of heated debate. Other routes (intrahepatic, intraperitoneal) are still to be proven and not recommendable outside the trial setting. The latest results of chemotherapy combinations with biological treatments (bevacuzimab and cetuximab) have been very promising indeed. Further improvements in survival, response and qu

Topics: Antimetabolites, Antineoplastic; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colorectal Neoplasms; Deoxycytidine; Drug Therapy, Combination; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Tegafur; Uracil; Vitamin B Complex

Neoadjuvant radiochemotherapy in patients suffering from pancreatic cancer is presently not well established. Neoadjuvant radiochemotherapy is recommended to be applied in 5-8 weeks. The full dose of radiotherapy is between 50 and 54 Gy with 5FU used as radiosensitator. In patients with resectable pancreatic cancer, particularly in UICC-stage II neoadjuvant radiochemotherapy, this results in an improvement in survival: the median survival is between 15 and 30 months. In about 15% of the patients with resectable pancreatic cancer (UICC I-III), neoadjuvant radiochemotherapy results in downstaging. In combination with a R0-resection,neoadjuvant radiochemotherapy effects a reduction of local recurrence. Results from controlled clinical trials are necessary to objectify the benefits of neoadjuvant radiochemotherapy.

Topics: Adult; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Case-Control Studies; Child; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Controlled Clinical Trials as Topic; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Neoadjuvant Therapy; Neoplasm Metastasis; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Prospective Studies; Radiation-Sensitizing Agents; Radiotherapy Dosage; Streptozocin; Time Factors

Systemic chemotherapy has a key role in the palliative treatment of patients with metastatic colorectal cancer. Compared to best supportive care, 5-fluorouracil (5-FU)-based therapy prolongs survival and improves quality of life. 5-FU continuous infusion modulated by Leukovorin (LV) is the optimal basis for a combination therapy with irinotecan or oxaliplatin. Randomized trials investigating the role of irinotecan in combination with 5-FU/LV relative to 5-FU/LV alone demonstrated a significant improvement in the response rate, progression free survival and overall survival. Randomized studies using oxaliplatin/ 5-FU/LV vs. FU/LV alone resulted in a higher response rate and longer progression-free survival while the overall survival was not significantly different. Today, all patients should receive combination treatment in first line and should be offered all active compounds during the course of their disease. Hereby, median survival times of more than 20 months are achievable. The use of oral fluoropyrimidines as a substitute of infusional 5-FU in combination with irinotecan or oxaliplatin is promising and subject of clinical trials. Monoclonal antibodies directed against the EGF-receptor or against VEGF have demonstrated interesting results and may be a treatment option in the future.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Disease Progression; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Neoplasm Staging; Palliative Care; Survival Rate

Metastatic colorectal cancer is a major cause of cancer-related mortality. Surgical resection of all known metastatic disease can be curative in selected patients. The majority of patients, however, require the consideration of systemic chemotherapy as optimal palliative treatment for their diseases. Using new effective chemotherapeutic agents such as irinotecan and oxaliplatin has resulted in a clear and clinically significant improvement in survival for patients with metastatic colorectal cancer. The optimal sequences and combinations of these agents as initial and salvage chemotherapy along with 5-fluorouracil (5-FU) and leucovorin are controversial. It seems clear that it is important for all patients to have access to all 3 drugs at some point in their therapy for optimal results. Recent randomized trials of first-line chemotherapy for metastatic colorectal cancer in which patients were likely to have access to all 3 effective drugs demonstrated median survivals of 18-20 months. This compares favorably to median survivals of approximately 12 months for patients treated with 5-FU-based regimens alone prior to the availability of effective salvage therapy. A small but meaningful number of patients might develop resectable disease with curative intent as the result of significant tumor response to combination chemotherapy. Herein, we review recent developments in combination and sequential chemotherapy for metastatic colorectal cancer and the implications for the optimal treatment in these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Salvage Therapy; Survival Rate

Up until now the standard treatment for metastasized colorectal carcinoma has been fluorouracil (5-FU) in combination with folonic acid in low doses administered intravenously, even after the recent registration of a number of new intravenously administered cytostatics, such as irinotecan and oxaliplatin. Meanwhile there are oral alternatives for 5-FU: capecitabine and the combination of tegafur and uracil with folonic acid. In four randomised studies it was shown that these drugs were globally just as effective as the combination of 5-FU with folonic acid (in accordance with the 'Mayo Clinic' scheme). There was no survival advantage for the oral drugs compared to 5-FU with folonic acid. Compared to 5-FU and folonic acid the use of capecitabine or tegafur-uracil-folonic acid was associated with less toxic effects; however, there were differences in the side effects profile between the oral drugs and 5-FU (more hand-foot syndrome for capecitabine and less (symptomatic) leucopenia for tegafur-uracil-folonic acid). An examination of the serious side effects (grade 3 and 4) revealed that the total incidence was generally comparable. These data, together with the ease of oral administration, form the basis for the registration of capecitabine and tegafur-uracil-folonic acid. The definitive place of these drugs in the treatment of metastasized colorectal carcinoma is not yet clear.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Pyrimidines; Tegafur; Uracil

Metastatic colorectal cancer has long been considered as a short-term, poor prognosis, chemoresistant disease. Until the early 1990s, the impact of systemic chemotherapy on patient outcome was debated. Recently, the emergence of new therapeutic modalities (5-FU modulations and associations with oxaliplatin and irinotecan) has led to a significant improvement in tumor response rates and patient survival. Thus, the indications of curative surgery of visceral metastases, frequently preceded and followed by chemotherapy, systemic or intra-arterial or both, have become more frequent. In this paper we will review and comment on the results of the major clinical trials published in the past 5 years and propose some decision strategies regarding the main clinical situations met in daily practice.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Camptothecin; Clinical Trials as Topic; Colorectal Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Methotrexate; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

Preclinical evidence of a schedule-dependent synergism between raltitrexed and 5-fluorouracil (5-FU) has prompted clinical studies of this combination. We review the main preclinical and clinical results of raltitrexed/5-FU-based combination chemotherapy regimens in anticancer therapy. Promising results include: response rates of 25 and 23% with combinations of raltitrexed/5-FU/levofolinic acid (LFA) as first-line treatment and oxaliplatin/raltitrexed/5-FU/LFA as second-line treatment of metastatic colorectal cancer, respectively; and a 67% response rate in a phase I study of cisplatin/raltitrexed/5-FU/LFA as first-line treatment of advanced head and neck cancer, including a 100% response rate at the recommended dose. These combinations were well tolerated, with neutropenia as the main dose-limiting toxicity, allowing the drugs to be combined at the doses used in monotherapy. These results suggest a role for raltitrexed within combination regimens in colorectal cancer therapy, as well as other tumors such as head and neck cancer. A further potential application of raltitrexed in combination therapies is within multidisciplinary chemo-radiotherapy strategies, mainly in rectal cancer. Phase II studies are planned/ongoing to investigate these interesting possibilities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Neoplasm Metastasis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Rectal Neoplasms; Thiophenes

Capecitabine is an orally administered fluoropyrimidine which is selectively activated in tumour tissue to the active moiety fluorouracil and is cytotoxic through inhibition of DNA synthesis. In patients with advanced or metastatic colorectal cancer, first-line therapy with intermittent capecitabine achieved significantly higher objective tumour response rates than therapy with fluorouracil plus leucovorin in pooled analysis. Response rates were also higher in patients pretreated in the adjuvant setting and whose primary site of metastasis was the lung. However, no significant differences between the two treatment groups were seen in the time to disease progression, time to treatment failure or overall survival. Preliminary data suggest response may be improved by combining capecitabine with other anticancer therapies such as oxaliplatin, irinotecan and radiotherapy. Capecitabine in therapeutic dosage regimens generally has acceptable tolerability. Diarrhoea and hand-and-foot syndrome are the major dose-limiting toxicities associated with capecitabine therapy, with adverse effects generally of a gastrointestinal nature. Overall, diarrhoea, stomatitis, nausea and alopecia were significantly less common with capecitabine than with bolus fluorouracil and leucovorin. In addition, capecitabine recipients experienced significantly less myelosuppression, although more capecitabine recipients discontinued therapy because of adverse events. Importantly, patients spent less time in hospital after capecitabine than after bolus fluorouracil and leucovorin therapy, and the oral route of administration of capecitabine is likely to be preferred. In conclusion, capecitabine has shown superior tumour response and less myelosuppression, although more grade 3 hand-and-foot syndrome, in comparison with the 'Mayo Clinic' regimen of fluorouracil therapy, but is unlikely to improve survival. Significantly, its oral route of administration is likely to be preferred by patients. Future strategies to improve patient response may involve selection of those patients likely to respond best to capecitabine, through determination of relevant enzyme levels and combination of capecitabine with various antineoplastic agents. Data on the effect of the drug on quality of life would help establish its role. In the meantime, capecitabine appears to offer an effective and more convenient alternative to fluorouracil as first-line monotherapy for the treatment of metastatic colorectal cancer.

Topics: Absorption; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Drug Interactions; Enzyme Induction; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Survival Analysis; Up-Regulation

Irinotecan (Camptosar) is a topoisomerase I inhibitor with demonstrated antitumor activity against a wide variety of malignancies. Phase II studies have shown that this agent has significant single-agent activity against both chemotherapy-naive and fluorouracil (5-FU)-refractory colorectal cancer. Phase III studies now indicate that irinotecan/5-FU/leucovorin combinations have antitumor activity superior to standard 5-FU/leucovorin regimens alone. These irinotecan-based combinations are now entering clinical trials for the adjuvant treatment of resected stage III colon cancer. It is hypothesized that the superior antitumor activity of these irinotecan-based combinations seen in the metastatic setting will translate into improved survival and increased cure rates in these earlier-stage patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome

Two randomized phase III trials with irinotecan as second-line treatment of metastatic colorectal cancer have shown that irinotecan (CPT-11, Camptosar) significantly improves survival when compared with best supportive care or continuous infusion of fluorouracil (5-FU) after failure of 5-FU. The combination of irinotecan and 5-FU/leucovorin produced a significantly higher response rate (40.8% vs 23.1%, P < .001), longer time to progression of disease (6.7 vs 4.4 months, P < .001), longer median survival (17.4 vs 14.1 months, P = .03), and a greater chance of survival at 1 year (69% vs 59%, P = .03) than 5-FU/leucovorin treatment alone. Such benefits have not previously been demonstrated in this setting. Although the use of irinotecan in combination with 5-FU/leucovorin increased the likelihood of neutropenia, the incidence of febrile neutropenia and infection remained low. Other toxic effects were manageable, noncumulative, and reversible.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome

Oxaliplatin was first introduced to the clinical setting as a combination therapy with 5-fluorouracil/folinic acid (5-FU/FA) in an attempt to improve the response rate obtained with 5-FU/FA against colorectal cancer. To dispel the impression that the improvements observed in objective response were somehow due to the chronomodulated regimen used, oxaliplatin was also tested in constant-rate infusion schedules and in regimens using bolus administration followed by 5-FU/FA infusion. The most current data comparing chronomodulated infusion and constant-rate infusion in untreated patients show a lower objective response rate for the latter (51 % v 29%), but comparable median progression-free survival and median survival (9.8 months and 15.9 months v 7.9 months and 16.9 months, respectively). The first trials using constant-rate therapy included pretreated patients with metastatic colorectal cancer, most of whom were refractory to 5-FU. In these studies, conducted using two different regimens or variations of them, objective response rates < or = 46% were obtained. The addition of oxaliplatin to 5-FU/FA in controlled, randomized phase III trials has resulted in a twofold or greater increase in objective response rate and a 3-month gain in time to progression, with survival differences blurred by crossover effect. Compassionate-use programs that included many heavily pretreated relapsing patients reported response rates of 15% to 25%, confirming the value of the oxaliplatin-5-FU/FA regimen and suggesting that oxaliplatin may act synergistically with 5-FU.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

The introduction of oxaliplatin into the colorectal cancer setting represents a significant advancement in the treatment of the disease. Synergistic effects with traditional therapy 5-fluorouracil/folinic acid have increased response rates significantly, improved time-sensitive response parameters, and facilitated the removal of previously unresectable hepatic metastases, thus changing the natural history of the disease. Ongoing and planned trials are identifying various issues that need to be addressed to fully realize the potential of oxaliplatin. These include optimization of dosing and schedule of administration, determination of the most effective oxaliplatin-5-fluorouracil/folinic acid combination, definition of the role of new thymidylate synthase inhibitors with respect to oxaliplatin therapy, and identification of the most effective combinations of oxaliplatin with the new anticancer agents that have been recently introduced. Providing the answers to these questions will contribute to changing the attitude of the clinical oncologist regarding what strategy to adopt in treating colorectal cancer in the coming years.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Drug Administration Schedule; Enzyme Inhibitors; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Thymidylate Synthase

Since its introduction in 1953, 5-fluorouracil based chemotherapy remained the standard treatment in advanced colorectal cancer. Continuous infusion or biochemical modulation by folinic acid enhanced the therapeutic efficacy of this agent. Quality of life is limited by the toxicity of these regimens as well as by the frequent visits to the hospital during each cycle. Raltitrexed, a thymidylate synthase inhibitor, offers similar antitumoral activity together with a tolerability in comparison to standard 5-fluorouracil based chemotherapy and its simple dosage schedule also contributes to better quality of life. New chemotherapeutic agents are currently in development for the treatment of patients refractory to 5-fluorouracil. Irinotecan and oxaliplatin demonstrate promising activity.

Topics: Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Colonic Neoplasms; Enzyme Inhibitors; Fluorouracil; Hospitalization; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Quality of Life; Quinazolines; Rectal Neoplasms; Thiophenes; Thymidylate Synthase; Topoisomerase I Inhibitors

As a single agent, irinotecan has demonstrated efficacy in metastatic 5FU resistant colorectal metastatic cancer. Chemotherapy with fluorouracil (5FU) plus leucovorin remains a standard in the treatment of patients with metastatic colorectal cancer. It seemed logical to test the combination of this reference treatment and the new agent. The first trials gave rather disappointing results, suggesting an inhibition of the metabolism of irinotecan into SN38 when 5FU was present in the circulation. More recent studies have given totally different results with a very good tolerance and strong efficacy of the combination of weekly folinic acid + 5FU and irinotecan or LV5FU2 (the so-called de Gramont regimen) and irinotecan. The results were so good that these new schedules are currently developed as first line regimen. Another way to combine 5FU, folinic acid and irinotecan is to alternate a cycle of 5FU, folinic acid and a cycle of irinotecan. Such an alternated schedule has given encouraging results with an objective response rate greater than 30% and a long median survival time (more than 16 months). It is also very easy to combine irinotecan with other drug which have demonstrated activity in the treatment of colorectal cancer. The combinations of irinotecan and mitomycin C or oxaliplatin have given very good results with high objective response rates and good tolerance. Irinotecan plays now an important part in the treatment of metastatic colorectal cancer. This part becomes larger due to the results of the combination trials already presented which have shown strong efficacy and good tolerance.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Enzyme Inhibitors; Europe; Fluorouracil; Irinotecan; Japan; Leucovorin; Mitomycin; Neoplasm Metastasis; Neoplasm Proteins; Organoplatinum Compounds; Oxaliplatin; Topoisomerase I Inhibitors; Treatment Outcome; United States

Combinations of active antineoplastic agents have been the most effective treatment for metastatic breast cancer. Criteria for an effective combination include use of drugs with different mechanisms of action, nonoverlapping toxic effects, and synergistic, or at least additive, antitumor activity. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), with its unique mechanism of action, offers an excellent opportunity for development of effective combination therapy against breast cancer. However, a number of problems have hindered the rapid development of effective combinations. The most obvious problem is the lack of a defined optimal dose and schedule of administration. The second problem has been the demonstration of unexpected interactions between paclitaxel and the other component(s) of the combination, often resulting in unusual and serious toxic effects. This review will focus on the phase I and II trials of paclitaxel in combination with established antineoplastic drugs (except doxorubicin and congeners, which is covered elsewhere in this issue) for breast cancer: cisplatin, 5-fluorouracil with or without folinic acid, cyclophosphamide, radiation therapy, as well as novel investigational agents or strategies, edatrexate, monoclonal antibodies to oncogenes, growth factors, and gene therapy with insertion of multidrug resistance gene into blood stem cells. Combination therapy offers exciting possibilities of enhanced antitumor efficacy. However, given the unexpected and serious toxic effects observed, only proven combinations should be used outside the context of a clinical trial. Additionally, the burden of proof will be to show that these combinations have increased antitumor activity, decreased toxicity, or both compared with single-agent paclitaxel.

Topics: Aminopterin; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Synergism; Drugs, Investigational; Female; Fluorouracil; Genetic Therapy; Humans; Leucovorin; Neoplasm Metastasis; Oncogenes; Paclitaxel; Radiotherapy, Adjuvant

Topics: Adult; Age Factors; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Preoperative Care; Quality of Life; Radiotherapy Dosage; Radiotherapy, Adjuvant; Rectal Neoplasms; Risk Factors; Semustine; Sex Factors; Vincristine

Pancreatic, gastric, and colorectal carcinomas are diagnosed in 200,000 Americans each year. Therapeutic options for patients with advanced disease are limited; conventional chemotherapy is palliative and produces complete responses in only a few patients. Clinical research has focused on the evaluation of investigational new drugs, combination regimens, and biochemical modulation of fluorouracil. Unfortunately, the results of recent phase II studies of new agents have been disappointing. The exception is CPT-11, a topoisomerase I inhibitor, which showed promising activity in colorectal cancer (in including patients who had failed prior fluorouracil therapy). Modified regimens of fluorouracil and methotrexate with either doxorubicin alone or with epirubicin and cisplatin were associated with response rates approaching 50% in patients with gastric cancer, but appeared to be less toxic than previously published regimens. A randomized trial comparing fluororacil alone or with oral leucovorin allowed early dose escalation according to individual tolerance; the response rate to fluorouracil alone (23%) was higher than that reported in previous phase III trials, suggesting the importance of using adequate doses to produce toxicity in terms of clinical response. Hepatic arterial infusion of floxuridine was associated with a 39% response rate in colorectal cancer patients with disease confined to the liver for whom systemic fluorouracil therapy had failed, suggesting this approach is a reasonable therapeutic option in carefully selected patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Combined Modality Therapy; Digestive System Neoplasms; Double-Blind Method; Drugs, Investigational; Gastrointestinal Neoplasms; Humans; Immunologic Factors; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Neoplasm Metastasis; Pancreatic Neoplasms; Prospective Studies; Survival Rate; Treatment Outcome

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Colonic Neoplasms; Fluorouracil; Humans; Interferons; Leucovorin; Methotrexate; Neoplasm Metastasis; Phosphonoacetic Acid; Rectal Neoplasms

17 patients with metastasizing colorectal cancer were treated in a phase II-study with systemic intravenous chemotherapy (Petrelli N, Proc ASCO 286, 1987) consisting of leucovorin 500 mg/m2 in a 2 hr infusion and 5-fluorouracil (5-FU) 600 mg/m2 bolus one hour after the commencement of the leucovorin infusion. Limiting toxicities were gastrointestinal, in form of nausea/vomiting of WHO grade 3 (n = 1) and of diarrhoea of maximal grade 4 (n = 5), as well as haematological with a maximal nadir of leucocytes of WHO grade 4 (n = 1) and of thrombocytes of WHO grade 1 (n = 1). Of the 14 evaluable patients an objective response was achieved in 21% of cases (CR: n = 1, PR: n = 2). 64% of the patients showed no change and 14% showed progression of their disease, 7 out of the 17 patients have died; the median survival was 24 months. With respect to objective remission, our result of 21% response rate is lower than the median of 32% of 24 different studies comprising 695 patients; nevertheless, the present response rate is within the range observed in the published studies of between 0% and 67%. In order to estimate the antitumoral efficacy of the new regimen 5-FU/leucovorin more objectively, a retrospective comparison of the therapy regimens used most frequently in disseminated colorectal cancer (5-FU monotherapy, 5-FU/methotrexate (MTX), 5-FU/MTX/low dose leucovorin, 5-FU/cisplatin, 5-FU/leucovorin) has been performed. The continuous administration of 5-FU monotherapy, with an objective response rate of 26%, was superior to standard 5-FU monotherapy as a bolus injection or short-term infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diarrhea; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Survival Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Methotrexate; Neoplasm Metastasis; Remission Induction

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Doxorubicin; Extremities; Humans; Leucovorin; Methods; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Prognosis; Prostheses and Implants; Random Allocation

First prognostic factors which are relevant for the variable course of bladder carcinoma like histological grading, blood group antigens and multiplicity of bladder tumors are discussed. Furthermore, therapy and recidive prophylaxis of not infiltrating carcinoma by intravesical cytostatic chemotherapy are discussed. In contrast to Thiotepa, a substance which has now been used for 20 years by many oncologists and should not be used any more because of very frequent systemic toxicity and only variable effects against the tumor, Adriamycin, Mitomycin C and Epodyl reduce the frequency of recidives used as prophylactic therapy after transurethral resection. With these substances pronounced systemic toxicity has not been seen until now. Cisdiaminodichloroplatin is a cytostatic agent which is also effective used systemically in cases with generalized bladder carcinoma. Used in combination with Adriamycin and Cyclophosphamide, remission rates could be increased to 80%. On the other hand toxicity is pronounced and the prolongation of survival times could not be proved until now as no results of controlled studies are available at this moment.

Topics: Antineoplastic Agents; BCG Vaccine; Cisplatin; Doxorubicin; Ethoglucid; Humans; Leucovorin; Methotrexate; Mitomycins; Neoplasm Metastasis; Neoplasm Recurrence, Local; Teniposide; Thiotepa; Urinary Bladder Neoplasms

MTX-CF therapy was administered in 13 patients with advanced renal cell carcinoma. 2 patients were treated with MTX single agent therapy at a dosage of up to 750mg/m2 per cycle and a short CF rescue of 48 hours. They showed partial remissions along with severe toxicity including gastrointestinal symptoms and bone marrow depression. 11 patients were treated by combination of MTX/CF, vincristine, bleomycin and an alkylating agent (either peptichemio or cyclophosphamide). In this latter group, patients with a glomerular filtration rate of more than 70 ml/min received 150 to 400 mg/m2 per cycle MTX. Patients with decreased renal function (glomerular filtration rate less than 70 ml/min) received 35 to 100 mg/m2 per cycle MTX. Two out of 7 patients with decreased glomerular filtration rate achieved remissions of more than 50%, two achieved remissions of less than 50% and two patients achieved static disease. Only one patient in the group of 4 patients with normal renal function showed a remission of more than 50%. Median survival time of patients in partial remission or with static disease was 24 months, of patients showing progression was 5 months. This difference is highly significant (p < 0.001). These results seem to justify further investigations of MTX/CF therapy in hypernephromas, even in the presence of impaired renal function.

Topics: Adenocarcinoma; Alkylating Agents; Bleomycin; Drug Therapy, Combination; Humans; Kidney Neoplasms; Leucovorin; Methotrexate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Vincristine

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Agents; Bone Neoplasms; Cell Division; Child; Clinical Trials as Topic; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Prognosis; Radiotherapy, High-Energy; Time Factors

Topics: Adult; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Child; Cyclophosphamide; Doxorubicin; Drug Combinations; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunotherapy; Leucovorin; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasms; Osteosarcoma; Prednisone; Rhabdomyosarcoma; Testicular Neoplasms; Thiotepa; Vinblastine; Vincristine

Topics: Adolescent; Adult; Alkalies; Aminopterin; Animals; Bone Marrow; Bone Neoplasms; Drug Therapy, Combination; Female; Folic Acid Antagonists; Humans; Kidney; Kidney Failure, Chronic; Leucovorin; Leukemia L1210; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Thymidine; Vincristine

This paper presents an overview of studies of therapy of head and neck squamous cell carcinoma in which chemotherapy was combined with other modalities. The rationale for using chemotherapy with surgery is discussed, but ststematic studies of this combination of modalities have not been reported. Systemic chemotherapy plus radiation therapy has been studied using hydrozyurea, t-fluorouracil (5-FU), and methotrexate (MTX). Uncontrolled studies with hydroxyurea report favorable results, but a well-controlled study gave negative results. Controlled studies with 5-FU have given favorable results in certain tumor stages and sites of origin. MTX plus radiation in a small series produced slightly better survival than radiation alone. Intra-arterial chemotherapy plus radiation therapy has been the subject of exploratory studies but no firm conclusions can be drawn from these studies. Chemotherapy plus immunotherapy has been explored and merits further study. Based on the studies reported to date one can suggest the need for large-scale randomized control studies of long-term chemotherapy combined with other modalities.

Topics: Bleomycin; Carcinoma, Squamous Cell; Cyclophosphamide; Fluorouracil; Head; Head and Neck Neoplasms; Humans; Hydroxyurea; Immunotherapy; Laryngeal Neoplasms; Leucovorin; Methotrexate; Neoplasm Metastasis; Neoplasms; Radiotherapy; Vinblastine

Topics: Adjuvants, Pharmaceutic; Adult; Animals; Bone Neoplasms; Child; Doxorubicin; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Humans; Immunotherapy; Leucovorin; Methotrexate; Neoplasm Metastasis; Osteosarcoma

Whether triplet chemotherapy is superior to doublet chemotherapy in advanced biliary tract cancer (BTC) is unknown.. In this open-label, randomized phase II-III study, patients with locally advanced or metastatic BTC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive oxaliplatin, irinotecan, and infusional fluorouracil (mFOLFIRINOX), or cisplatin and gemcitabine (CISGEM) for a maximum of 6 months. We report the results of the phase II part, where the primary end point was the 6-month progression-free survival (PFS) rate among the patients who received at least one dose of treatment (modified intention-to-treat population) according to Response Evaluation Criteria in Solid Tumors version 1.1 (statistical assumptions: 6-month PFS rate ≥ 59%, 73% expected).. A total of 191 patients (modified intention-to-treat population, 185: mFOLFIRINOX, 92; CISGEM, 93) were randomly assigned in 43 French centers. After a median follow-up of 21 months, the 6-month PFS rate was 44.6% (90% CI, 35.7 to 53.7) in the mFOLFIRINOX arm and 47.3% (90% CI, 38.4 to 56.3) in the CISGEM arm. Median PFS was 6.2 months (95% CI, 5.5 to 7.8) in the mFOLFIRINOX arm and 7.4 months (95% CI, 5.6 to 8.7) in the CISGEM arm. Median overall survival was 11.7 months (95% CI, 9.5 to 14.2) in the mFOLFIRINOX arm and 13.8 months (95% CI, 10.9 to 16.1) in the CISGEM arm. Adverse events ≥ grade 3 occurred in 72.8% of patients in the mFOLFIRINOX arm and 72.0% of patients in the CISGEM arm (toxic deaths: mFOLFIRINOX arm, two; CISGEM arm, one).. mFOLFIRINOX triplet chemotherapy did not meet the primary study end point. CISGEM doublet chemotherapy remains the first-line standard in advanced BTC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Cisplatin; Deoxycytidine; Disease Progression; Female; Fluorouracil; France; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Progression-Free Survival; Time Factors

The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC).. We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes.. In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS.. TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Cell Cycle Proteins; Colonic Neoplasms; DNA Replication; DNA-Binding Proteins; Female; Fluorouracil; Germ-Line Mutation; Humans; Intracellular Signaling Peptides and Proteins; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Survival Rate

Cetuximab in combination with chemotherapy is a standard first-line treatment regimen for patients with metastatic colorectal cancer (mCRC) RAS wild-type (wt); however, the efficacy of cetuximab plus leucovorin, fluorouracil and oxaliplatin (FOLFOX) had never been demonstrated in a prospective, randomized, controlled phase III study. The TAILOR study is the first randomized, multicenter, prospective Phase III study evaluating the addition of cetuximab to FOLFOX in a RAS wt Chinese population and thus providing confirmatory data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Prospective Studies; Rectal Neoplasms

Chemotherapy dose modification to manage adverse events is commonplace in clinical practice. This exploratory analysis evaluates the impact of liposomal irinotecan dose modification on overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 clinical trial (NCT01494506).. Analysis includes only patients enrolled under protocol version 2 who received at least the first 2 scheduled doses of study drug. Within the liposomal irinotecan +5 fluorouracil/leucovorin (5 FU/LV) arm, patients were grouped according to whether or not they had a dose modification within the first 6 weeks. Dose reduction was defined as any decrease from initial dose; dose delay was any dosing delay >3 days from target date. OS and PFS (Kaplan-Meier estimates) were compared within the liposomal irinotecan+5-FU/LV arm and between treatment arms. Unstratified hazard ratios (HRs) were calculated using Cox regression analysis.. Of the 93 patients from the liposomal irinotecan+5 FU/LV arm included in the analysis, 53 experienced a dose modification (both delay and reduction, n = 30; delay only, n = 19; reduction only, n = 4). No apparent difference in median OS or PFS was observed between patients who did versus patients who did not have a dose modification (OS: 8.4 vs 6.7 months; HR, 0.89; PFS: 4.2 vs 3.1 months; HR, 0.74).. An early dose reduction or delay of liposomal irinotecan+5-FU/LV in the first 6 weeks does not significantly impact OS or PFS compared to patients without dose modifications. This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Survival Analysis

Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen.. The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled.. NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6-8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma, Neuroendocrine; Etoposide; Female; Fluorouracil; Humans; Intestinal Neoplasms; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Neoplasms, Unknown Primary; Neuroendocrine Tumors; Oxaliplatin; Pancreatic Neoplasms; Platinum Compounds; Progression-Free Survival; Prospective Studies; Quality of Life; Stomach Neoplasms; Survival Rate; Treatment Outcome

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Survival Rate

Metastatic pancreatic cancer (mPC) still harbors a dismal prognosis. Our previous trial (PRODIGE 4-ACCORD 11) demonstrated the superiority of 6-month chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) over gemcitabine for overall survival. The high limiting oxaliplatin-related neurotoxicity supports the evaluation of an oxaliplatin stop-and-go strategy and a sequential strategy in mPC.. In this phase II study, patients were randomly assigned to receive either 6 months of FOLFIRINOX (arm A), 4 months of FOLFIRINOX followed by leucovorin plus fluorouracil maintenance treatment for controlled patients (arm B), or a sequential treatment alternating gemcitabine and fluorouracil, leucovorin, and irinotecan every 2 months (arm C). The primary end point was progression-free survival at 6 months.. Between January 2015 and November 2016, 276 patients (mean age: 63 years; range: 40-76 years) were enrolled (A: 91, B: 92, and C: 90). Grade 3 or 4 neurotoxicity occurred in 10.2% of patients in arm A and 19.8% in arm B. The median ratio of received dose/targeted dose of oxaliplatin was 83% in arm A and 92% in arm B. The 6-month progression-free survival was 47.1% in A, 42.9% in B, and 34.1% in C. The median overall survival was 10.1 months in arm A, 11.2 in arm B, and 7.3 in arm C. Median survival without deterioration in quality-of-life scores was higher in the maintenance arm (11.4 months) than in arms A and C (7.2 and 7.5 months, respectively).. Maintenance with leucovorin plus fluorouracil appears to be feasible and effective in patients with mPC controlled after 4 months of induction chemotherapy with FOLFIRINOX. Severe neurotoxicity was higher in the maintenance therapy arm, probably because of the higher cumulative dose of oxaliplatin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Quality of Life

In locally advanced or metastatic biliary tract cancer (BTC), second-line chemotherapy is challenging after progression from first-line gemcitabine/cisplatin. This study evaluated whether irinotecan/5-fluorouracil (5-FU; mFOLFIRI) was superior to oxaliplatin/5-FU (mFOLFOX) as a second-line treatment in BTC.. Patients diagnosed with BTC with disease progression after prior gemcitabine/cisplatin were randomised (1:1) to either mFOLFOX (control arm) or mFOLFIRI (experimental arm). Randomisation was stratified by tumour location (intrahepatic versus extrahepatic versus gallbladder versus ampulla of Vater) and ECOG performance status (0, 1 versus 2). The primary endpoint was the overall survival (OS) rate at 6 months.. In total, 120 patients were enrolled and 118 patients were randomised (mFOLFOX n = 59, mFOLFIRI n = 59). The baseline characteristics were well balanced between the two arms. The tumour location was intrahepatic bile duct in 48 patients (40.7%), extrahepatic bile duct in 29 patients (24.6%), gallbladder in 35 patients (29.7%) and ampulla of Vater in 6 patients (5.1%). At a median follow-up duration of 25.8 months, the 6-month OS rate was 54.1% in mFOLFOX and 44.1% in mFOLFIRI (p = 0.677). The median OS was 6.3 months (95% CI, 4.4-8.2) in mFOLFOX and 5.7 months (95% CI, 4.7-6.7) in mFOLFIRI (p = 0.677). The median progression-free survival was 2.8 months (95% CI, 2.3-3.3) in mFOLFOX and 2.1 months (95% CI, 1.1-3.1) in mFOLFIRI (p = 0.974). Of the 101 evaluable patients, the objective response rate and disease control rate were 5.9% and 66.7% in mFOLFOX and 4.0% and 64.0% in mFOLFIRI (p = 0.663 and p = 0.778, respectively). Peripheral neuropathy (37.5% versus 5.2%) and thrombocytopenia (35.7% versus 15.5%) in mFOLFOX and vomiting (19.0% versus 1.8%) and cholangitis (10.3% versus 0.0%) in mFOLFIRI occurred more frequently. No chemotherapy-related death was reported.. In the second-line treatment of BTC, mFOLFIRI was not superior to mFOLFOX. However, mFOLFIRI was tolerable and showed comparable efficacy to mFOLFOX. Adverse events were different between the two arms. CLINICALTRIALS.. NCT03464968.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Camptothecin; Cisplatin; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

The TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis.. In total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017.. With a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72-1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71-1.04, P < 0.0001 for non-inferiority). In patients with left-sided RAS wild-type tumours, median PFS durations were 11.4 and 16.9 months in the control and experimental groups, respectively (HR: 0.68, 95% CI: 0.48-0.96, P = 0.028).. S-1 and irinotecan plus bevacizumab resulted in comparable OS and non-inferior PFS with that of mFOLFOX6/CapeOX plus bevacizumab treatment as first-line chemotherapy for patients with mCRC. We recommend the use of S-1 and irinotecan plus bevacizumab as a standard first-line regimen independent of tumour sidedness or RAS status in mCRC.. UMIN-CTR: 000007834.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Genes, ras; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Oxonic Acid; Proto-Oncogene Proteins B-raf; Quality of Life; Tegafur

The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506).

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Endpoint Determination; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Platinum-based therapy is the standard of care in patients who have HER2-negative, advanced esophagogastric cancer (AEGC). Retrospective data suggest that intratumoral. Overall, 202 untreated patients with HER2-negative AEGC and a Zubrod performance status of 0-1 were evaluated prospectively for mRNA expression of. Eighty-six percent of patients had. The evaluation of

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; DNA-Binding Proteins; Endonucleases; Esophageal Neoplasms; Esophagogastric Junction; Female; Fluorouracil; Gene Expression; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Progression-Free Survival; Proportional Hazards Models; Prospective Studies; Stomach Neoplasms; Young Adult

Cetuximab-induced skin toxicity (Cet-ST) is positively associated with outcome in metastatic colorectal cancer (mCRC). Besides its predictive relevance for targeted therapy, we investigated its prognostic impact with early tumor shrinkage (ETS) ≥20%, another on-treatment surrogate for clinical outcome in FIRE-3.. FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumors (i.e. wild-type in KRAS and NRAS exons 2-4). Retrospective data on Cet-ST that occurred during cycles 1-3 of treatment were correlated with efficacy endpoints, including ETS. To control for guarantee-time bias, only patients who had completed three or more treatment cycles were considered.. Of 199 patients treated with FOLFIRI/Cet, 181 (91.0%) completed three or more treatment cycles. A significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was only evident in patients developing Cet-ST grade 2-3 [41.0 versus 26.6 months; hazard ratio (HR) = 0.73; 95% confidence interval (CI): 0.61-0.87; P < 0.001] compared with Cet-ST grade 0-1 (HR = 0.90; 95% CI: 0.67-1.20; P = 0.48). Regarding prognosis, Cet-ST grade 2-3 (n = 75; 41.4%), compared with Cet-ST grade 0-1 (n = 106; 58.6%), was associated with prolonged overall survival (OS; HR = 0.62; 95% CI: 0.42-0.91; P = 0.01). In multivariate analysis, both Cet-ST (HR = 0.66; 95% CI: 0.50-0.87; P = 0.003) and ETS (HR = 0.55; 95% CI: 0.41-0.74; P < 0.0001) were independently prognostic for OS. Absence of both Cet-ST grade ≥2 and ETS identified a subgroup of patients with very poor prognosis (median OS 15.1 months).. In FIRE-3, the addition of cetuximab to FOLFIRI was associated with superior OS compared with FOLFIRI/Bev only in patients developing Cet-ST grade ≥2. Regarding prognostic relevance, both Cet-ST and ETS were independent and early predictors of survival. The present analysis supports that a combined evaluation of on-treatment parameters such as Cet-ST and ETS may help to guide treatment of mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Retrospective Studies; Treatment Outcome

In spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed.. An open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS.. Phase-A enrolled 128 patients; median age was 64 years (range: 26-84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus ≤ 5 was 1.4 (95% CI: 0.9-2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9-10.8) for Phase-A and 6.7 months (95% CI: 3.0-8.2) for Phase-B. The HR for OS based on bNLR > 5 versus ≤ 5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2-29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group.. Results from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR.. ClinicalTrials.gov: NCT01588990; posted May 1, 2012.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Capecitabine; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Inflammation; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaloacetates; Prognosis; Translational Research, Biomedical

Bevacizumab, a VEGF-A inhibitor, in combination with chemotherapy, has proven to increase progression-free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin-2 (Ang-2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF-A and Ang-2, suggesting that the dual VEGF-A and Ang-2 blocker vanucizumab (RO5520985 or RG-7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX-6 (folinic acid (leucovorin), fluorouracil (5-FU) and oxaliplatin) versus bevacizumab/mFOLFOX-6 for first-line mCRC.. All patients received mFOLFOX-6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator-assessed PFS.. One hundred eighty-nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64-1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang-2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm.. Vanucizumab/mFOLFOX-6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX-6. Our results suggest that Ang-2 is not a relevant therapeutic target in first-line mCRC.. This randomized phase II study demonstrates that additional angiopoietin-2 (Ang-2) inhibition does not result in superior benefit over anti-VEGF-A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang-2 is not a relevant therapeutic target in the clinical setting of treatment-naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF-A and Ang-2 inhibitor vanucizumab was discontinued.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

The least toxic time (LTT) of irinotecan varied by up to 8 hours according to sex and genetic background in mice. The translational relevance was investigated within a randomized trial dataset, where no LTT stood out significantly in the whole population. 130 male and 63 female eligible patients with metastatic colorectal cancer were randomized to receive chronomodulated Irinotecan with peak delivery rate at 1 of 6 clock hours staggered by 4 hours on day 1, then fixed-time chronomodulated Fluorouracil-Leucovorin-Oxaliplatin for 4 days, q3 weeks. The sex-specific circadian characteristics of grade (G) 3-4 toxicities were mapped with cosinor and time*sex interactions confirmed with Fisher's exact test. Baseline characteristics of male or female patients were similar in the six treatment groups. Main grade 3-4 toxicities over six courses were diarrhea (males vs females, 39.2%; vs 46.0%), neutropenia (15.6% vs 15.0%), fatigue (11.5% vs 15.9%), and anorexia (10.0% vs 7.8%). They were reduced following irinotecan peak delivery in the morning for males, but in the afternoon for females, with statistically significant rhythms (P < .05 from cosinor) and sex*timing interactions (Fisher's exact test, diarrhea, P = .023; neutropenia, P = .015; fatigue, P = .062; anorexia, P = .032). Irinotecan timing was most critical for females, with grades 3-4 ranging from 55.2% of the patients (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. The study results support irinotecan administration in the morning for males and in the afternoon for females, in order to minimize adverse events without impairing efficacy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Prognosis; Sex Characteristics; Survival Rate

In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints.. We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively.. BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (- 57.6% vs. - 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1-4.4) vs. 3.9 (95% CI 2.5-5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9-8.0) versus 2.6 (95% CI 1.2-4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11-0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0-41.3) vs. 5.4 (95% CI 5.0-5.9) months; HR 0.27 (95% CI 0.13-0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site.. BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Proto-Oncogene Proteins B-raf; ras Proteins; Treatment Outcome

This phase II study tested granulocyte-macrophage colony-stimulating factor (GM-CSF)-allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting.. Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8-12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for four doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms.. Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median OS was 9.38 months [95% confidence interval (CI), 5.0-12.2] for Arm A and 14.7 months (95% CI, 11.6-20.0) for Arm B (HR, 1.75;. GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Ipilimumab; Irinotecan; Leucovorin; Macrophages; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Tumor Microenvironment

Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1.. To evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients.. In this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival.. Overall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed.. In patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.

Topics: Active Transport, Cell Nucleus; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Hydrazines; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Prognosis; Survival Rate; Triazoles

Chemotherapy is effective in metastatic pancreatic adenocarcinoma (mPA), but new approaches are still needed to improve patients' survival and quality of life. We have previously published good efficacy and tolerability results on a sequential treatment strategy of gemcitabine followed by an intensified FOLFIRI (5FU+irinotecan) regimen. In the present study, we evaluated the same sequence but replaced gemcitabine by the new gemcitabine + nab-paclitaxel standard first-line combination.. We randomised chemotherapy-naive patients with proven mPA, bilirubin levels ≤1.5 upper limit of normal values and performance status 0-2 to alternately receive gemcitabine + nab-paclitaxel for 2 months then FOLFIRI.3 for 2 months in arm A, or gemcitabine + nab-paclitaxel alone until progression in arm B. The primary objective was to increase the 6-month progression-free survival (PFS) rate from 40% (H. Between November 2015 and November 2016, 127 patients were enrolled. Main grade III-IV toxicities (% in arm A/B) were: diarrhoea (12.5/1.7), neutropenia (46.9/31, including febrile neutropenia: 1.6/0), skin toxicity (6.3/13.8), and peripheral neuropathy (6.3/8.6). No toxic deaths occurred. The objective response rate was 40.3% (95% confidence interval [CI]: 28.1-53.6) in arm A and 26.7% (95% CI: 16.1-39.7) in arm B. The primary end-point (6-month PFS rate) was 45.2% [one-sided 95% CI: 34.3-56.4] in arm A and 23.3% in arm B [one-sided 95% CI: 14.3-32.3] in the mITT population. In the PP population, median PFS and OS were 7.6 months and 6 months and 14.5 months and 12.2 months in arm A and B, respectively.. The FIRGEMAX strategy with gemcitabine + nab-paclitaxel alternating with FOLFIRI.3 every 2 months, appears feasible and effective, with manageable toxicities, in patients able to reach >2mo of treatment.. EudraCT: 2014-004449-28: NCT: 0282701.

Topics: Adenocarcinoma; Adult; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease Progression; Drug Substitution; Female; Fluorouracil; France; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Treatment Outcome

Quality of life (QoL) patient-reported outcomes (PROs) data from pivotal first-line trials in metastatic colorectal cancer (mCRC) are poor. The Valentino study showed that de-escalation to single-agent panitumumab after 4-month induction with panitumumab-FOLFOX is inferior to panitumumab-5-FU/LV in patients with RAS wild-type mCRC, although slightly reducing toxicity. We report QoL, a secondary end-point.. PROs were assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30), EORTC QLQ-CR29, EuroQol EQ-5D questionnaires, at baseline and every 8 weeks until disease progression. First two evaluations correspond to induction treatment (identical in both arms), while subsequent to maintenance. To describe QoL changes over time, mean changes from baseline at each time point were calculated in overall population. To compare maintenance between two arms, mean changes and proportion of improved/stable/worse patients versus baseline were compared for each item.. In arm A/B, 91.5%/92.0% of enrolled patients completed questionnaires at baseline. No significant differences in the two arms were reported in compliance, baseline scores and mean changes versus baseline for the three questionnaires during maintenance (24/32/40 weeks). Overall, mean changes versus baseline showed an early deterioration during induction with partial recovering during maintenance for global QoL, functional scales and several symptoms/items of QLQ-C30 (fatigue, nausea/vomiting, appetite loss, diarrhoea) and QLQ-CR29 (body image, dry mouth, hair loss, taste, faecal incontinence, sore skin), and EQ-5D Visual Analogue Scale (VAS) score.. In patients with RAS wild-type mCRC, induction with oxaliplatin-containing chemotherapy plus anti-EGFRs induces a transient significant QoL deterioration. After induction phase, treatment deintensification determines an overall recovery of health-related QoL, besides the expected prevention of oxaliplatin-related neurotoxicity.

Topics: Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; Female; Fluorouracil; Genes, ras; Humans; Italy; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Patient Reported Outcome Measures; Progression-Free Survival; Quality of Life; Time Factors

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility of patients to irinotecan and its toxicity. This study is a multicenter, randomised clinical trial comparing the clinical outcomes and adverse events (AEs) in metastatic colorectal cancer (mCRC) patients treated with bevacizumab plus FOLFIRI with or without UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy.. The control group received conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 genotyping, whereas the study group received the same regimen with irinotecan dose escalation based on UGT1A1 genotyping. The primary end-point was progression-free survival (PFS), and secondary end-points were overall response rate (ORR), disease control rate (DCR), overall survival (OS), AEs and metastasectomy rate.. Over a median follow-up of 26.0 months (IQR, 17.0-35.0 months), study group (n = 107) was superior to the control group (n = 106) in PFS, OS, ORR, DCR, and metastasectomy rate (all P < 0.05). Furthermore, there were no significant differences in AEs ≥ grade III between the two groups, even with the 1.36-fold increase in the relative dose intensity of irinotecan in the study group. Dose escalation of irinotecan, an independent factor of ORR (P < 0.001) and DCR (P = 0.006), improved PFS in mCRC patients with wild-type and mutant KRAS (P = 0.007 and P = 0.019, respectively).. The current study revealed that mCRC patients, regardless of KRAS gene status, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favourable clinical outcome without significantly increased toxicities.. NCT02256800.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Outcome Assessment, Health Care; Polymorphism, Genetic; Proto-Oncogene Proteins p21(ras)

The phase III West Japan Oncology Group (WJOG) 4407G study showed noninferiority of folinic acid, bolus/continuous fluorouracil, and irinotecan plus bevacizumab to modified folinic acid, bolus/continuous fluorouracil, and oxaliplatin 6 plus bevacizumab in progression-free survival (PFS) as first-line chemotherapy for patients with metastatic colorectal cancer. The aim of this study was to evaluate the predictive and prognostic value of morphologic response in patients with colorectal liver metastases (CLM) as a post hoc analysis of the WJOG4407G study.Morphologic response was assessed by comparing contrast-enhanced computed tomography (CT) images at baseline and week 8. Three blinded radiologists evaluated CT images and classified their response as optimal, incomplete, or no response according to the morphologic criteria. Response evaluation criteria in solid tumors (RECIST) response, early tumor shrinkage (ETS), and depth of response (DpR) were also evaluated.Among 395 patients who were eligible for efficacy analysis in the WJOG4407G study, 70 patients had liver-limited disease. We finally evaluated 55 of these patients. Optimal morphologic response was identified in 19 of 55 patients (34.5%). The median PFS was 10.7 months for patients with optimal response and 10.1 months in those with incomplete/no response (log-rank, P = .96). The median overall survival (OS) was 26.2 and 35.5 months, respectively (log-rank, P = .062). According to univariate analysis, morphologic response was not associated with PFS or OS, whereas RECIST response was significantly associated with both PFS and OS, with ETS and DpR being associated with significantly longer PFS.Morphologic response might be neither a predictive nor a prognostic factor in patients with CLM undergoing chemotherapy containing bevacizumab, whereas RECIST response was significantly associated with both PFS and OS.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Japan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Predictive Value of Tests; Prognosis; Progression-Free Survival; Response Evaluation Criteria in Solid Tumors; Tomography, X-Ray Computed; Topoisomerase I Inhibitors; Treatment Outcome; Vitamin B Complex

Oligometastatic disease (OMD) identifies tumours with limited metastatic spread. OMD definition is not univocal and no data from clinical trials are available about the prognostic effect of OMD in metastatic colorectal cancer (mCRC), the impact of locoregional treatments (LRTs) and the effect of chemotherapy intensification in these patients. The role of tumour burden (TB) in driving therapeutic choices is also debated.. We performed a pooled analysis of phase III TRIBE and TRIBE2 studies comparing FOLFOXIRI/bevacizumab (bev) to doublets (FOLFOX or FOLFIRI)/bev. Patients were grouped in OMD versus non-OMD based on the European Society for Medical Oncology definition. Among patients with OMD, those with OMD/low TB were compared with all the others.. Of 1187 patients enrolled, 1096 were classified as OMD (N = 312 [28%]) or non-OMD (N = 784 [72%]). Among patients with OMD, 126 (40%) were OMD/low TB. OMD was associated with longer progression-free survival (14.0 versus 10.1 months; p < 0.01) and overall survival (38.2 versus 22.0 months; p < 0.01). These results were confirmed in multivariable models. The benefit provided by FOLFOXIRI/bev compared with doublets/bev did not differ in accordance with OMD and TB (p for interaction >0.05). Patients with OMD underwent LRTs more frequently (p < 0.01) and those with OMD/low TB had higher chance to undergo LRTs after the first progression (p < 0.01).. OMD is a positive prognostic factor in mCRC. The benefit from the upfront treatment intensification is independent of the metastatic spread extent and TB. LRTs should be highly considered in these patients, mainly during the first-line therapy but also at later stages of treatment history in selected cases.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Progression-Free Survival; Tumor Burden; Young Adult

In the NAPOLI-1 phase 3 trial, liposomal irinotecan (nal-IRI) +5-fluorouracil/leucovorin (5-FU/LV) significantly increased mPFS versus 5-FU/LV (3.1 vs. 1.5 months [unstratified HR = 0.56, p = 0.0001]) in patients with mPAC that progressed on prior gemcitabine-based therapy. This randomized phase 2 trial evaluated nal-IRI+5-FU/LV tolerability (Part 1), safety, and efficacy (Part 2; outcomes reported here) in Japanese patients with mPAC that progressed on gemcitabine-based therapy.. Patients were randomized 1:1 and stratified by KPS (70 and 80 vs. ≥90) and baseline albumin (≥4.0 g/dl vs. <4.0 g/dl). Primary endpoint was PFS; secondary endpoints were ORR, DCR, OS, TTF, CA19-9 response, and QoL. The ITT population comprised all randomized patients.. Patient characteristics differed between nal-IRI+5-FU/LV (n = 40) and 5-FU/LV (n = 39) arms, including baseline hepatic lesions (63% vs. 51%), stage IV disease at diagnosis (78% vs. 51%), and post-study anticancer therapy (55% vs. 72%). Investigator-assessed mPFS increase with nal-IRI+5-FU/LV was clinically meaningful and statistically significant versus 5-FU/LV (2.7 vs. 1.5 months, HR = 0.60). Independently assessed mPFS showed similar trends (1.7 vs. 1.6 months, HR = 0.79). mOS was 6.3 months with nal-IRI+5-FU/LV and not reached with 5-FU/LV. ORR increased significantly with nal-IRI+5-FU/LV versus 5-FU/LV (18% vs. 0, rate difference 17.5). Commonly reported grade ≥3 treatment-emergent AEs were decreased neutrophil count (37% vs. 3%), decreased white blood cell count (20% vs. 0), and diarrhea (17% vs. 3%).. In conclusion, clinically meaningful and statistically significant gains in investigator-assessed PFS and ORR were observed with nal-IRI+5-FU/LV versus 5-FU/LV in Japanese patients, with no new or unexpected safety signals. (Clinicaltrials.gov ID: NCT02697058).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Resistance, Neoplasm; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Japan; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pancreatic Neoplasms; Survival Rate

Fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence.. Chemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety.. In total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval [CI], 38.1-54.9) and 9.1 months (95% CI, 8.6-11.1) in group A, compared with 47.4% (80% CI, 39.1-55.8) and 9.3 months (95% CI, 6.0-13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%).. Planned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab.. NCT02337946.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Panitumumab; Peripheral Nervous System Diseases; Treatment Outcome

Survival in metastatic colorectal cancer is worse than expected in the United Kingdom. Real-world data are needed to better understand UK-specific treatment practices that may explain this.. The Avastin ColORectal Non-interventional (ACORN) study is a multicenter, prospective, UK-based, observational, phase 4 study (ClinicalTrials.gov, NCT01506167) that recruited patients with metastatic colorectal cancer scheduled to receive bevacizumab in combination with first-line chemotherapy as part of routine clinical practice. Primary end points included progression-free survival, overall survival (OS), serious adverse events (AEs), and grade 3 to 5 bevacizumab-related AEs.. A total of 714 patients were recruited between August 30, 2012, and February 4, 2014. Median follow-up was 16.4 months. Median first-line chemotherapy duration was 5.6 months, with capecitabine/oxaliplatin (265 [37.1%]) being the most common regimen. Median total chemotherapy duration was 8.1 months and did not vary by geographic location in the UK. Median progression-free survival (95% confidence interval) was 8.7 (8.2-9.1) months, and median OS was 17.8 (16.1-19.3) months. There was no significant difference in efficacy by chemotherapy regimen administered. Ninety-nine patients (13.9%) received bevacizumab after disease progression. The safety profile of bevacizumab was consistent with previous studies.. ACORN provided evidence that there were no clear differences observed in outcomes between bevacizumab with capecitabine-based chemotherapy and fluorouracil-based regimens, and confirmed the safety profile of bevacizumab in a real-world UK-based population. The lower-than-expected OS is likely due to the short total chemotherapy duration, less frequent use of bevacizumab after disease progression, and higher rates of in-situ primary tumors.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate; United Kingdom

The phase III TRIBE and TRIBE2 studies randomized metastatic colorectal cancer patients to first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI or FOLFOX)/bevacizumab. The studies demonstrated a significant benefit from the triplet at the price of an increased incidence of chemotherapy-related adverse events (AEs). In both trials, males and females aged between 18 and 70 years with ECOG PS ≤2 and between 71 and 75 years with ECOG PS = 0 were eligible. We investigated the effect of FOLFOXIRI/bevacizumab versus doublets/bevacizumab according to age and gender.. Subgroup analyses according to age (<70 versus 70-75 years) and gender were carried out for overall response rate (ORR), progression-free survival (PFS), and AE rates.. Of 1187 patients, 1005 (85%) were aged <70 years and 182 (15%) 70-75 years; 693 (58%) were males and 494 (42%) females. There was no evidence of interaction between age or gender and the benefit provided by the intensification of the upfront chemotherapy in terms of ORR and PFS, or the increased risk of experiencing G3/4 AEs. Elderly patients and females experienced higher rates of overall G3/4 AEs (73% versus 60%, P < 0.01 and 69% versus 57%, P < 0.01, respectively). Notably, in the FOLFOXIRI/bevacizumab subgroup, G3/4 diarrhea and febrile neutropenia occurred in 27% and 16% of elderly patients, respectively, while females reported high incidences of any grade nausea (67%) and vomiting (50%).. The improvements in terms of ORR and PFS of FOLFOXIRI/bevacizumab versus doublets/bevacizumab are independent of gender and age, with a similar relative increase in AEs among elderly patients and females. Initial dose reductions and possibly primary G-CSF prophylaxis should be recommended for patients between 70 and 75 years old treated with FOLFOXIRI/bevacizumab, and a careful management of antiemetic prophylaxis should be considered among females.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Nausea; Neoplasm Metastasis; Organoplatinum Compounds; Progression-Free Survival; Sex Characteristics; Treatment Outcome; Vomiting

MiR-31-3p expression has been shown to be associated with response to anti-EGFR therapy. We investigated the predictive role of this biomarker in the FIRE-3 study population, including its ability to differentiate outcomes between patients receiving anti-EGFR and anti-VEGF therapy.. MiR-31-3p expression was measured in primary tumors obtained from 340 patients with. Low miR-31-3p expressers benefited from cetuximab compared with bevacizumab for PFS [HR, 0.74; 95% confidence interval (CI), 0.55-1.00;. MiR-31-3p expression level was validated as a predictive biomarker of cetuximab therapy efficacy for patients with

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Leucovorin; MicroRNAs; Middle Aged; Neoplasm Metastasis; Progression-Free Survival; Young Adult

: Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters.. Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum.. RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276).. In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant.. NCT01183780.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Mutation; Neoplasm Metastasis; Neovascularization, Pathologic; Prognosis; Proto-Oncogene Proteins c-raf; Ramucirumab; ras Proteins; Survival Rate

Second-line treatment with chemotherapy plus bevacizumab or cetuximab is a valid option for metastatic colorectal cancer.. To evaluate the progression-free survival (PFS) rate at 4 months with chemotherapy plus bevacizumab vs cetuximab for patients with progression of metastatic colorectal cancer after bevacizumab plus chemotherapy.. A prospective, open-label, multicenter, randomized phase 2 trial was conducted from December 14, 2010, to May 5, 2015. The main eligibility criterion was disease progression after bevacizumab plus fluorouracil with irinotecan or oxaliplatin in patients with wild-type KRAS exon 2 metastatic colorectal cancer. All analyses were performed on the modified intent-to-treat population.. Patients were randomized to arm A (FOLFIRI [fluorouracil and folinic acid combined with irinotecan] or modified FOLFOX6 [fluorouracil and folinic acid combined with oxaliplatin] plus bevacizumab) or arm B (FOLFIRI or modified FOLFOX6 plus cetuximab); the second-line chemotherapy regimen was chosen according to first-line treatment (crossover).. The primary end point was the 4-month PFS rate. Secondary end points included safety, objective response rate, overall survival, and PFS.. A total of 132 patients (47 women and 85 men; median age, 63.0 years [range, 33.0-84.0 years]; 74 patients with an Eastern Cooperative Oncology Group performance status of 0, 54 patients with a performance status of 1, and 4 patients with unknown performance status) were included at 25 sites. The 4-month PFS rate was 80.3% (95% CI, 68.0%-88.3%) in arm A and 66.7% (95% CI, 53.6%-76.8%) in arm B. The median PFS was 7.1 months (95% CI, 5.7-8.2 months) in arm A and 5.6 months (95% CI, 4.2-6.5 months) in arm B (hazard ratio, 0.71; 95% CI, 0.50-1.02; P = .06), and the median overall survival was 15.8 months (95% CI, 9.5-22.3 months) in arm A and 10.4 months (95% CI, 7.0-16.2 months) in arm B (hazard ratio, 0.69; 95% CI, 0.46-1.04; P = .08). A central analysis of KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF (V600) was performed for 95 tumor samples. Eighty-one patients had wild-type KRAS and wild-type NRAS tumors.. The results of the PRODIGE18 (Partenariat de Recherche en Oncologie DIGEstive) study showed a nonsignificant difference but favored continuation of bevacizumab with chemotherapy crossover for patients with wild-type RAS metastatic colorectal cancer that progressed with first-line bevacizumab plus chemotherapy.. ClinicalTrials.gov identifier: NCT01442649 and clinicaltrialsregister.eu identifier: EUDRACT 2009-012942-22.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Cetuximab; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Progression-Free Survival; Prospective Studies; Proto-Oncogene Proteins p21(ras); Time Factors

The NAPOLI-1 study (NCT01494506) reported that liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) improved overall survival vs 5-FU/LV with manageable toxicity in patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy. Yet, clinicians need treatment strategies that also maintain the patient's health-related quality of life (HRQOL). Here, we report the HRQOL data.. Patients completed the European Organisation for Research and Treatment of Cancer QOL core questionnaire C30 (EORTC QLQ-C30) at baseline, every 6 weeks, and at 30 days after discontinuation of study treatment. Patient-reported outcomes (PROs) were scored according to EORTC guidelines. nal-IRI+5-FU/LV HRQOL was compared with 5-FU/LV. The PRO population comprised intent-to-treat patients who completed baseline and at least one subsequent assessment on the EORTC QLQ-C30. Data were also analysed for missingness.. Of 236 patients in the intent-to-treat population, 128 (54.2%) comprised the PRO population (71 in the nal-IRI+5-FU/LV arm; 57 the in 5-FU/LV arm). Of the remaining 108 patients (45.8%) not included in the PRO population, most progressed rapidly, making participation difficult. Median change from baseline was ≤10 points at weeks 6 and 12 in global health status or functional and symptom scale scores, except for fatigue, which deteriorated by 11.1 points with nal-IRI+5-FU/LV but did not change vs 5-FU/LV. The proportion of patients whose HRQOL improved or deteriorated was not significantly different between the arms.. In the NAPOLI-1 study, HRQOL was maintained with nal-IRI+5-FU/LV in patients with metastatic pancreatic adenocarcinoma previously treated with a gemcitabine-based regimen, while survival was significantly extended.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Patient Reported Outcome Measures; Progression-Free Survival; Quality of Life; Time Factors

Metastatic colorectal cancer (mCRC) has low survival rates. We assessed if addition of veliparib, concurrent to FOLFIRI, improves survival in patients with previously untreated mCRC.. This study compared veliparib (200 mg BID for 7 days of each 14-day cycle) to placebo, each with FOLFIRI. Bevacizumab was allowed in both arms. The primary endpoint was progression-free survival (PFS).. Patients were randomised to receive veliparib (n = 65) or placebo (n = 65) in combination with FOLFIRI. Median PFS was 12 vs 11 months (veliparib vs placebo) [HR = 0.94 (95% CI: 0.60, 1.48)]. Median OS was 25 vs 27 months [HR = 1.26 (95% CI: 0.74, 2.16)]. Response rate was 57% vs 62%. Median DOR was 11 vs 9 months [HR = 0.73 (95% CI: 0.38, 1.40)]. AEs with significantly higher frequency (p < 0.05) in the veliparib group were anaemia (39% vs 19%, p = 0.019) and neutropenia (66% vs 37%, p = 0.001) for common AEs (≥20%); neutropenia (59% vs 22%, p < 0.001) for common Grade 3/4 AEs (≥5%); none in serious AEs. Haematopoietic cytopenias were more common with veliparib (79% vs 52%, p = 0.003). Fourteen percent of patients on veliparib and 15% on placebo discontinued treatment due to AEs.. Veliparib added to FOLFIRI ± bevacizumab demonstrated similar efficacy as FOLFIRI ± bevacizumab in frontline mCRC patients. No unexpected safety concerns occurred.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Progression-Free Survival

Epidermal growth factor receptor signalling blockade increases CCL5 expression that regulates either the anti-tumour immune response or tumour progression. We investigated the potential role of CCL5/CCR5 axis in cetuximab-based treatment in metastatic colorectal cancer (mCRC) patients.. Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC from the FIRE-3 trial: an evaluation cohort of 244 patients receiving cetuximab plus FOLFIRI and a control cohort of 247 patients receiving bevacizumab plus FOLFIRI. Single-nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analysed by polymerase chain reaction-based direct sequencing.. Patients in the evaluation cohort with any CCL5 rs2280789G allele had shorter overall survival (OS) compared with those with the A/A variant (hazard ratio 1.56, P = 0.024). Patients carrying any CCR5 rs1799988T allele had a trend toward lower response rate than those with the C/C variant (68 vs. 81%, P = 0.078). In the analysis based on primary tumour location (left-sided [L]: right-sided [R]), remarkable differences in outcomes were observed between patients with L-CCR5 SNPs C/C variant (L-C/C), L-any T, R-T/T and R-any C as follows: median OS, 38.5, 30.6, 27.1 and 15.8 months, P < 0.001; response rate, 91, 66, 92 and 48%, P < 0.001. Median OS for CCL5 SNPs including L-A/A, L-any G, R-A/A and R-any G groups were 38.3, 21.7, 21.9 and 18.3 months, P < 0.001. The findings were not significant in the control cohort.. Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC patients receiving cetuximab-based treatment depending on tumour location.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Case-Control Studies; Cetuximab; Chemokine CCL5; Cohort Studies; Colorectal Neoplasms; ErbB Receptors; Female; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Polymorphism, Single Nucleotide; Prognosis; Receptors, CCR5; Survival Rate

Based on our pre-clinical data, we hypothesized that sequencing chemotherapy with erlotinib would increase the tumor response rate in patients with metastatic colorectal cancer.. A phase II trial (planned n=58) using second-line therapy for metastatic colorectal cancer with either oxaliplatin-based (mFOLFOX6) or irinotecan-based (FOLFIRI) combination chemotherapy and 100 mg erlotinib daily on days 3-8 after each infusion (days 1 and 2) every 14 days. The primary endpoint was the response rate compared to the historical response rate.. The FOLFIRI/erlotinib arm met the pre-specified response rate criteria of at least 10% to expand accrual to the intended sample size. The trial was halted after an interim safety analysis (n=11) due to excess grade 3 neutropenia, dose reductions and treatment delays. Grade 3 or 4 neutropenia was observed in 64% of patients. The response rate was 18%.. In second-line treatment for metastatic colorectal cancer, mFOLFOX6 or FOLFIRI with erlotinib in a sequence-dependent fashion is not feasible despite potential promising activity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Erlotinib Hydrochloride; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

Aflibercept in combination with 5‑fluorouracil (5‑FU)/irinotecan improves overall survival in the second‑line therapy of patients with metastatic colorectal cancer (mCRC). In this study, we evaluated the effects of aflibercept in first‑line therapy with FOLFOX followed by maintenance with fluoropyrimidine. VELVET was a prospective, single‑arm multicenter phase II study (completed). Patients with previously untreated, unresectable, evaluable or measurable mCRC, with an age ≥18 years, and an ECOG performance status of 0‑2 received 6 cycles of modified FOLFOX7 (5‑FU/folinic acid and oxaliplatin) with aflibercept at 4 mg/kg every 2 weeks followed by maintenance therapy with fluoropyrimidine with aflibercept until disease progression or limiting toxicity. The reintroduction of oxaliplatin was performed at first progression. The primary endpoint was progression‑free survival (PFS) at 6 months. From May, 2013 to May, 2014, 49 patients were included and 48 were evaluable for response. In total, 33 patients (67.4%) were alive without progression at 6 months. The Kaplan‑Meier survival 6‑month and 1‑year PFS rates were 79.1 and 36.1%, respectively, and the median PFS was 9.3 months (95% CI, 8.3‑12.5). The objective response rate was 59.2% (N=29/49). The most common (≥10%) grade 3‑4 adverse events were hypertension (23%), fatigue (15%), neutropenia (12%), neuropathy (12%) and stomatitis (10%). Three (6%) treatment‑related deaths occurred: One from stroke, one from pulmonary embolism and one from neutropenic sepsis. On the whole, this study demonstrates the efficacy of aflibercept in combination with an oxaliplatin‑based regimen in the first‑line therapy of patients with mCRC. A strict monitoring of blood pressure and immediate management of hypertension during therapy is mandatory.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prospective Studies; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Survival Analysis; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Costs; Female; Fluorouracil; France; Health Status; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prospective Studies; Quality of Life; Surveys and Questionnaires

Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC).. Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS).. PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm.. Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Immunohistochemistry; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Survival Rate

Several studies show the importance of accurately quantifying not only KRAS and other low-abundant mutations because benefits of anti-EGFR therapies may depend on certain sensitivity thresholds. We assessed whether ultra-selection of patients using a high-sensitive digital PCR (dPCR) to determine KRAS, NRAS, BRAF and PIK3CA status can improve clinical outcomes of panitumumab plus FOLFIRI.. This was a single-arm phase II trial that analysed 38 KRAS, NRAS, BRAF and PIK3CA hotspots in tumour tissues of irinotecan-resistant metastatic colorectal cancer patients who received panitumumab plus FOLFIRI until disease progression or early withdrawal. Mutation profiles were identified by nanofluidic dPCR and correlated with clinical outcomes (ORR, overall response rate; PFS, progression-free survival; OS, overall survival) using cut-offs from 0% to 5%. A quantitative PCR (qPCR) analysis was also performed.. Seventy-two evaluable patients were enrolled. RAS (KRAS/NRAS) mutations were detected in 23 (32%) patients and RAS/BRAF mutations in 25 (35%) by dPCR, while they were detected in 7 (10%) and 11 (15%) patients, respectively, by qPCR. PIK3CA mutations were not considered in the analyses as they were only detected in 2 (3%) patients by dPCR and in 1 (1%) patient by qPCR. The use of different dPCR cut-offs for RAS (KRAS/NRAS) and RAS/BRAF analyses translated into differential clinical outcomes. The highest ORR, PFS and OS in wild-type patients with their lowest values in patients with mutations were achieved with a 5% cut-off. We observed similar outcomes in RAS/BRAF wild-type and mutant patients defined by qPCR.. High-sensitive dPCR accurately identified patients with KRAS, NRAS, BRAF and PIK3CA mutations. The optimal RAS/BRAF mutational cut-off for outcome prediction is 5%, which explains that the predictive performance of qPCR was not improved by dPCR. The biological and clinical implications of low-frequent mutated alleles warrant further investigations.. NCT01704703.. 2012-001955-38.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Fluorouracil; Genotype; GTP Phosphohydrolases; Humans; Leucovorin; Male; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Panitumumab; Prospective Studies; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Survival Rate

Upfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes.. This open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician's discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates.. This is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM.. Clinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016-001865-99 .

Topics: Adult; Bevacizumab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Perioperative Period; Peritoneal Neoplasms; Peritoneum; Progression-Free Survival; Quality of Life

To determine the predictive and prognostic value of the consensus molecular subtypes (CMSs) of colorectal cancer (CRC) that represent a merging of gene expression-based features largely in primary tumors from six independent classification systems and provide a framework for capturing the intrinsic heterogeneity of CRC in patients enrolled in CALGB/SWOG 80405.. CALGB/SWOG 80405 is a phase III trial that compared the addition of bevacizumab or cetuximab to infusional fluorouracil, leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan as first-line treatment of advanced CRC. We characterized the CMS classification using a novel NanoString gene expression panel on primary CRCs from 581 patients enrolled in this study to assess the prognostic and predictive value of CMSs in these patients.. The CMSs are highly prognostic for overall survival (OS;. These findings highlight the possible clinical utility of CMSs and suggests that refinement of the CMS classification may provide a path toward identifying patients with metastatic CRC who are most likely to benefit from specific targeted therapy as part of the initial treatment.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Predictive Value of Tests; Prognosis; Treatment Outcome

Curcumin is the main active ingredient of the spice turmeric, investigated extensively for putative anticancer properties.. This phase IIa open-labelled randomized controlled trial aimed to assess safety, efficacy, quality of life, neurotoxicity, curcuminoids, and C-X-C-motif chemokine ligand 1 (CXCL1) in patients receiving folinic acid/5-fluorouracil/oxaliplatin chemotherapy (FOLFOX) compared with FOLFOX + 2 g oral curcumin/d (CUFOX).. Twenty-eight patients aged >18 y with a histological diagnosis of metastatic colorectal cancer were randomly assigned (1:2) to receive either FOLFOX or CUFOX. Safety was assessed by Common Toxicity Criteria-Adverse Event reporting, and efficacy via progression-free survival (PFS) and overall survival (OS). Quality of life and neurotoxicity were assessed using questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and Functional Assessment of Cancer Treatment-Gynecologic Oncology Group-Neurotoxicity). Plasma curcuminoids were determined with liquid chromatography (LC) electrospray ionization tandem mass spectrometry and CXCL1 by ELISA.. Addition of daily oral curcumin to FOLFOX chemotherapy was safe and tolerable (primary outcome). Similar adverse event profiles were observed for both arms. In the intention-to-treat population, the HR for PFS was 0.57 (95% CI: 0.24, 1.36; P = 0.2) (median of 171 and 291 d for FOLFOX and CUFOX, respectively) and for OS was 0.34 (95% CI: 0.14, 0.82; P = 0.02) (median of 200 and 502 d for FOLFOX and CUFOX, respectively). There was no significant difference between arms for quality of life (P = 0.248) or neurotoxicity (P = 0.223). Curcumin glucuronide was detectable at concentrations >1.00 pmol/mL in 15 of 18 patients receiving CUFOX. Curcumin did not significantly alter CXCL1 over time (P = 0.712).. Curcumin is a safe and tolerable adjunct to FOLFOX chemotherapy in patients with metastatic colorectal cancer. This trial was registered at clinicaltrials.gov as NCT01490996 and at www.clinicaltrialsregister.eu as EudraCT 2011-002289-19.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Curcumin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), compared with FOLFIRI alone, in patients with metastatic colorectal cancer previously treated with oxaliplatin-based therapy. This subset analysis of the VELOUR study investigates aflibercept plus FOLFIRI versus placebo plus FOLFIRI according to age.. Efficacy and safety were analyzed by treatment arm and age (≥ or <65years).. Overall, 443 patients were ≥65years old (205 in aflibercept arm; 238 in placebo arm) and 783 were <65years old (407 in aflibercept arm; 376 in placebo arm). Median OS was 12.6 versus 11.3months (hazard ratio [HR]: 0.85; 95.34% CI 0.68-1.07) in patients ≥65years old and 14.5 versus 12.5months (HR: 0.80; 95.34% CI 0.67-0.95) in those patients <65years old, for patients receiving FOLFIRI plus aflibercept or placebo, respectively. There was no interaction between treatment and age. Treatment-emergent adverse events (AEs) were comparable for patients <65years and ≥65years old. The incidence of grade 3/4 AEs was higher for patients ≥65years old than for those <65years old in both the aflibercept (89.3% versus 80.5%) and placebo (67.4% versus 59.4%) arms. Interaction tests for grade 3/4 antiangiogenic agent-related AEs suggested no heterogeneity between the older and younger patient populations (p>0.1).. A limited but consistent benefit on both OS and PFS was associated with the addition of aflibercept to FOLFIRI compared with placebo in patients <65 and ≥65years old, with a marked but manageable increase in the toxicity profile in older patients.. clinicaltrials.govNCT00561470.

Topics: Adenocarcinoma; Age Factors; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody-based therapy.. In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing.. A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P < 0.001) were comparable. Similar findings were observed for the median overall survival of RAS mutant and wild-type patients based on tissue (22.1 versus 35.8 months; P = 0.016) and plasma (19.9 versus 35.8 months; P = 0.013) analysis.. This study indicates that RAS testing of liquid biopsy results in a similar outcome when compared with tissue testing in mCRC patients receiving first-line anti-EGFR monoclonal antibodies.

Topics: Alleles; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liquid Biopsy; Mutation; Neoplasm Metastasis; Progression-Free Survival; Proto-Oncogene Proteins p21(ras); Treatment Outcome

Metastatic colorectal cancer frequently occurs in elderly patients. Bevacizumab in combination with front line chemotherapy (CT) is a standard treatment but some concern raised about tolerance of bevacizumab for these patients. The purpose of PRODIGE 20 was to evaluate tolerance and efficacy of bevacizumab according to specific end points in this population.. Patients aged 75 years and over were randomly assigned to bevacizumab + CT (BEV) versus CT. LV5FU2, FOLFOX and FOLFIRI regimen were prescribed according to investigator's choice. The composite co-primary end point, assessed 4 months after randomization, was based on efficacy (tumor control and absence of decrease of the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). For each arm, the treatment will be consider as inefficient if 20% or less of the patients met the efficacy criteria and not safe if 40% or less met the safety criteria.. About 102 patients were randomized (51 BEV and 51 CT), median age was 80 years (range 75-91). Primary end point was met for efficacy in 50% and 58% and for safety in 61% and 71% of patients in BEV and CT, respectively. Median progression-free survival was 9.7 months in BEV and 7.8 months in CT. Median overall survival was 21.7 months in BEV and 19.8 months in CT. The 36-month overall survival rate was 27% in BEV and 10.1% in CT. Severe toxicities grade 3/4 were mainly non-hematologic toxicities (80.4% in BEV, 63.3% in CT).. Bevacizumab combined with CT was safe and efficient. Both arms met the primary safety and efficacy criteria.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Survival Rate

The FIRE-3 trial investigated combination chemotherapy plus either cetuximab or bevacizumab in patients with untreated metastatic colorectal cancer (mCRC) not scheduled for upfront surgery. We aimed to determine the number of patients who present with potentially resectable disease during systemic first-line therapy and to compare the findings with study reports concerning resections and outcome.. This evaluation of 448 patients was performed as central review blinded for treatment, other reviewers' evaluations and conducted interventions. Resectability was defined if at least 50% of the reviewers recommended surgical-based intervention. Overall survival was assessed by Kaplan-Meier method.. Resectability increased from 22% (97/448) at baseline before treatment to 53% (238/448) at best response (P < 0.001), compared with an actual secondary resection rate for metastases of 16% (72/448). At baseline (23% versus 20%) and best response (53% versus 53%), potential resectability of metastases in this molecular unselected population was similar in cetuximab-treated patients versus bevacizumab-treated patients and not limited to patients with one-organ disease. The actual resection rate of metastases was significantly associated with treatment setting (P = 0.02; university hospital versus hospital/practice). Overall survival was 51.3 months (95% confidence interval [CI] 35.9-66.7) in patients with resectable disease who received surgery, 30.8 months (95% CI 26.6-34.9) in patients with resectable disease without surgery and 18.6 months (95% CI 15.8-21.3) in patients with unresectable disease (P < 0.001).. Our findings illustrate the potential for conversion to resectability in mCRC, certain reluctance towards metastatic resections in clinical practice and the need for pre-planned and continuous evaluation for metastatic resection in high-volume centres. CLINICALTRIALS.. NCT00433927.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Outcome Assessment, Health Care

The authors hypothesized that patients with metastatic colorectal cancer (mCRC) who had tumors with low thymidylate synthase (TS-L) expression would have a higher response rate to combined 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab (FOLFOX/Bev) than those with high TS (TS-H) expression and that combined irinotecan and oxaliplatin (IROX) plus bevacizumab (IROX/Bev) would be more effective than FOLFOX/Bev in those with TS-H tumors.. TS protein expression was determined in mCRC tissue. Patients who had TS-L tumors received FOLFOX/Bev, and those who had TS-H tumors were randomly assigned to receive either FOLFOX/Bev or IROX/Bev. The primary endpoint was the response rate (complete plus partial responses).. In total, 211 of 247 patients (70% TS-H) were registered to the treatment phase. Efficacy analyses included eligible patients who had started treatment (N = 186). The response rates for patients who received IROX/Bev (TS-H), FOLFOX/Bev (TS-H), and FOLFOX/Bev (TS-L) were 33%, 38%, and 49%, respectively (P = nonsignificant). The median progression-free survival (PFS) was 10 months (95% confidence interval [CI], 9-12 months; 10 months in the IROX/Bev TS-H group, 9 months in the FOLFOX/Bev TS-H group, and 13 months in the FOLFOX/Bev TS-L group). The TS-L group had improved PFS compared with the TS-H group that received FOLFOX/Bev (hazard ratio, 1.6; 95% CI, 1.0%-2.4%; P = .04; Cox regression). The median overall survival (OS) was 22 months (95% CI, 20 29 months; 18 months in the IROX/Bev TS-H group, 21 months in the FOLFOX/Bev TS-H group, and 32 months in the TS-L group). OS comparisons for the 2 TS-H arms and for the FOLFOX/Bev TS-H versus TS-L arms were not significantly different.. TS expression was prognostic: Patients with TS-L tumors who received FOLFOX/Bev had a longer PFS than those with TS-H tumors, along with a trend toward longer OS. Patients with TS-H tumors did not benefit more from IROX/Bev than from FOLFOX/Bev. Cancer 2018;124:688-97. © 2017 American Cancer Society.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Prognosis; Proportional Hazards Models; Thymidylate Synthase; Treatment Outcome

Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial.. Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution.. NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR].. This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymphocyte Count; Male; Middle Aged; Neoplasm Metastasis; Neutrophils; Organoplatinum Compounds; Prognosis; Retrospective Studies

Acne-like skin rash is a frequently occurring adverse event associated with drugs against the epidermal growth factor receptor. This randomized vehicle-controlled study investigated the addition of vitamin K1 cream to doxycycline in patients with metastatic colorectal cancer treated with cetuximab.. Patients receiving first-line cetuximab + FOLFIRI were randomly assigned to prophylactic treatment with doxycylin and vitamin K1 cream or doxycycline and the vehicle. The primary end point of the study was the incidence of grade ≥ 2 skin rash (NCI CTCAE version 4.02) during 8 weeks of skin treatment. Secondary end points comprised skin rash according to a more thorough tripartite skin toxicity score (WoMo), quality of life, efficacy, and compliance. The study had 80% power to show a 20% reduction of the incidence of grade ≥ 2 skin rash.. A total of 126 patients were analyzed. The incidence of skin rash grade ≥ 2 was comparable between the arms. Likewise, no difference was seen in the WoMo score with respect to the percentage of skin affected. However, starting in week 5 and increasing over time patients treated with vitamin K1 cream had less severe rash and fewer fissures. Quality of life as well as efficacy and compliance with study medication and anticancer treatment was comparable in both arms.. The primary end point of decreasing grade ≥ 2 skin rash was not met. However, using vitamin K1 cream as part of prophylactic treatment decreased the severity of acne-like skin rash according to WoMo, an alternative and more thorough skin toxicity scoring tool.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Double-Blind Method; Doxycycline; Exanthema; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Patient Compliance; Pharmaceutical Vehicles; Quality of Life; Skin Cream; Vitamin K 1; Young Adult

The combination of a triple-drug chemotherapy regimen with an anti-epidermal growth factor receptor (EGFR) agent as a first-line treatment of metastatic colorectal cancer (mCRC) showed promising activity along with safety concerns in single-arm phase 2 trials. The role of maintenance following chemotherapy and anti-EGFR and the optimal regimen to be adopted are not established.. To evaluate the activity and safety of cetuximab plus modified FOLFOXIRI (mFOLFOXIRI) and explore the role of maintenance with cetuximab or bevacizumab in RAS and BRAF wild-type mCRC.. In a prospective, noncomparative, open-label, multicenter, randomized phase 2 trial, patients aged 18 to 75 years with unresectable, previously untreated RAS and BRAF wild-type (before amendment, KRAS wild-type) mCRC were recruited from 21 oncology units in Italy from October 19, 2011, to March 1, 2015 (followed up through May 31, 2017). In total, 323 patients were screened and 143 were randomized to 2 treatment arms to receive as a first-line induction a regimen of mFOLFOXIRI plus cetuximab followed by cetuximab (arm A) or bevacizumab (arm B) until disease progression. Primary analyses were conducted in a modified intention-to-treat population.. mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles, followed by maintenance with cetuximab or bevacizumab until disease progression.. The primary end point was the 10-month progression-free rate (PFR); secondary end points included progression-free and overall survival, response rate, rate of metastases resection, and adverse events.. Of 143 patients randomized, 116 (81.1%) (median [interquartile range (IQR)] age, 59.5 [53-67] years; 34 [29.3%] women) had RAS and BRAF wild-type mCRC. At a median (IQR) follow-up of 44.0 (30.5-52.1) months, 10-month PFRs were 50.8% (90% CI, 39.5%-62.2%) in arm A and 40.4% (90% CI, 29.4%-52.1%) in arm B. The overall response rate was 71.6% (95% CI, 62.4%-79.5%). Main grade 3/4 adverse events were neutropenia (occurring in 36 patients [31%]), diarrhea (in 21 patients [18%]), skin toxic effects (in 18 patients [16%]), asthenia (in 11 patients [9%]), stomatitis (in 7 patients [6%]), and febrile neutropenia (in 3 patients [3%]).. Although neither of the 2 arms met the primary end point, the findings indicate that a 4-month induction regimen of mFOLFOXIRI plus cetuximab is feasible and provides relevant activity results, leading to a high surgical resection rate.. clinicaltrials.gov Identifier: NCT02295930.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Treatment Outcome; Young Adult

Older patients have frailty characteristics that impair the transposition of treatment results found in younger patients. Predictive factors are needed to help with treatment choices for older patients. The PRODIGE 20 study is a randomized phase II study that evaluated chemotherapy associated with bevacizumab (BEV) or not (CT) in patients aged 75 years or older.. Patients underwent a geriatric assessment at randomization and at each evaluation. The predictive value of geriatric and oncologic factors was determined for the primary composite end-point assessing safety and efficacy of treatment (BEV or CT) simultaneously and also progression-free survival (PFS) and overall survival (OS).. 102 patients were randomized (51 BEV and 51 CT; median age 80 years [range 75-91]). On multivariate analysis, baseline normal independent activity of daily living (IADL) score and no previous cardiovascular disease predicted the primary end-point. High (versus low) baseline Köhne score predicted short PFS and baseline Spitzer quality of life (QoL) score <8, albumin level ≤35 g/L, CA19.9 >2 LN levels above normal and high baseline Köhne score predicted short OS. Survival without deteriorated QoL and autonomy was similar with BEV and CT. On subgroup analyses, the benefit of bevacizumab seemed to be maintained in patients with baseline impaired IADL or nutritional status.. Normal IADL score was associated with a good efficacy and safety of both BEV and CT. Köhne criteria may be relevant prognostic factors in older patients. Adding bevacizumab to chemotherapy does not impair patient autonomy or QoL.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Survival Rate

Peritoneal carcinomatosis (PC) represents an unfavourable prognostic factor for patients with gastric cancer (GC). Intraperitoneal treatment with the bispecific and trifunctional antibody catumaxomab (EpCAM, CD3), in addition to systemic chemotherapy, could improve elimination of PC.. This prospective, randomised, phase II study investigated the efficacy of catumaxomab followed by chemotherapy (arm A, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel, FLOT) or FLOT alone (arm B) in patients with GC and PC. Primary endpoint was the rate of macroscopic complete remission (mCR) of PC at the time of second diagnostic laparoscopy/laparotomy prior to optional surgery.. Median follow-up was 52 months. Out of 35 patients screened, 15 were allocated to arm A and 16 to arm B. mCR rate was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects associated with catumaxomab were nausea, infection, abdominal pain, and elevated liver enzymes. Median progression-free (6.7 vs. 5.4 months, p = 0.71) and overall survival (13.2 vs. 13.0 months, p = 0.97) were not significantly different in both treatment arms.. Addition of catumaxomab to systemic chemotherapy was feasible and tolerable in advanced GC. Although the primary endpoint could not be demonstrated, results are promising for future investigations integrating intraperitoneal immunotherapy into a multimodal treatment strategy.

Topics: Adult; Aged; Antibodies, Bispecific; Antineoplastic Combined Chemotherapy Protocols; CD3 Complex; Docetaxel; Epithelial Cell Adhesion Molecule; Female; Fluorouracil; Gastrectomy; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Peritoneal Neoplasms; Stomach Neoplasms

Data from two trials of panitumumab in metastatic colorectal cancer (mCRC) were retrospectively analysed to investigate the effects of primary tumour location on early-tumour shrinkage (ETS) and depth of response (DpR), and identify factors predicting long-term survival.. Patients with RAS wild-type mCRC from PRIME (NCT00364013) and PEAK (NCT00819780) were included. ETS was defined as a ≥30% reduction in the sum-of-the-longest-diameters of measurable target lesions at eight weeks. DpR was the maximum percentage change from baseline to nadir in patients with shrinkage. Univariate and multivariate logistic analyses of short- versus long-term survivor data were performed.. A total of 435/559 (78%) patients had left-sided disease. Of these, a higher proportion of patients treated with panitumumab versus comparator achieved ETS (PRIME: 62% vs. 36%; PEAK: 58% vs. 41%); median DpR was also higher with panitumumab (PRIME: 59% vs. 49%; PEAK: 70% vs. 48%). In pooled analyses of the studies, more patients with right-sided disease achieved ETS if treated with panitumumab than comparator (39% vs. 29%). Panitumumab treatment consistently predicted long-term survival.. First-line panitumumab was associated with improved ETS and DpR vs. comparator in patients with left-sided mCRC. ETS may identify a subgroup of patients with right-sided disease who might respond to panitumumab.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; GTP Phosphohydrolases; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Retrospective Studies; Treatment Outcome

This multicentre, randomised, and phase II study evaluated mFOLFOX+cetuximab followed by maintenance mFOLFOX+cetuximab or single-agent cetuximab in metastatic colorectal cancer (mCRC) patients (NCT01161316).. Previously, untreated mCRC patients (wild-type KRAS) were randomised to receive cetuximab+mFOLFOX-6 (8 cycles for 2 weeks) followed by maintenance therapy: single-agent cetuximab (Arm-A) or mFOLFOX-6 + cetuximab (Arm-B) until progression. Primary endpoint was progression-free survival (PFS) at 9 months.. One hundred ninety-three patients (median [range] age 60 [33-74] years) were randomised (2:1): 129 Arm-A versus 64 Arm-B. PFS at 9 months (95% confidence interval) showed non-inferiority between arms (Arm-A/Arm-B: 60 [52, 69]%/72 [61, 83]%, p [non-inferiority]<0.1). There were no statistically significant differences in the PFS (Arm-A/Arm-B: 9 [95% CI 7, 10] months/10 [7,13] months, hazard ratio [HR] = 1.19 [0.80, 1.79]) or overall survival (23 [19, 28] months/27 [18, 36] months, HR = 1.24 [0.85, 1.79]) between arms. The objective response rate was also similar (48 [39, 57]%/39 [27, 52]%). The safety profile was similar between arms, and all patients experienced at least one adverse event (AE) (Arm-A/Arm-B grade ≥III AEs: 70%/68%). The most common grade ≥III AEs were as follows: neutropenia (Arm-A/Arm-B: 28%/26%), rash acneiform (15%/24%) and sensory neuropathy (2%/15%) in any group. Arm-A was associated with less grade ≥III rash and sensory neuropathy and a lower rate of serious AEs (20%/27%).. This phase II exploratory trial with a non-inferiority design suggests that maintenance therapy with single-agent cetuximab following mFOLFOX+cetuximab induction could be a valuable option compared with mFOLFOX+cetuximab treatment continuation. We await phase III trials to confirm single-agent cetuximab as maintenance therapy in mCRC patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Exanthema; Female; Fluorouracil; Humans; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras)

This analysis investigated the cost-effectiveness of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fluorouracil, and leucovorin) compared with bevacizumab plus mFOLFOX6 in the first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC).. The cost-effectiveness analysis was developed from a third-party payer perspective in the US and was implemented using a partitioned survival model with health states for first-line treatment (progression-free), disease progression with and without subsequent active treatment, and death. Survival analyses of patients with wild-type RAS mCRC from the PEAK head-to-head clinical trial of panitumumab vs bevacizumab were performed to estimate time in the model health states. Additional data from PEAK informed the amount of each drug consumed, duration of therapy, subsequent therapy use, and toxicities related to mCRC treatment. Literature and US public data sources were used to estimate unit costs associated with treatment and duration of subsequent active therapies. Utility weights were calculated from patient-level data from panitumumab trials in the first-, second-, and third-line settings. A life-time perspective was taken with future costs and outcomes discounted at 3% per annum. Scenario, one-way, and probabilistic sensitivity analyses were performed.. Compared with bevacizumab, the use of panitumumab resulted in an incremental cost of US $60,286, and an incremental quality-adjusted life-year (QALY) of 0.445, translating into a cost per QALY gained of US $135,391 in favor of panitumumab. Results were sensitive to wastage and dose rounding assumptions modeled.. Progression-free and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves. Costs and quality of life were estimated from multiple and different data sources.. The efficacy of panitumumab in extending progression-free and overall survival and improving quality of life makes it a cost-effective option for first-line treatment of patients with wild-type RAS mCRC compared with bevacizumab.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Cost-Benefit Analysis; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Models, Econometric; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Quality of Life; Quality-Adjusted Life Years; ras Proteins; Survival Analysis

To investigate whether the benefit of combining aflibercept with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) chemotherapy could be confirmed in patients from the Asia-Pacific region (ClinicalTrials.gov: NCT01661270). Patients & methods: Asian patients with oxaliplatin-pretreated metastatic colorectal cancer were randomized to receive aflibercept or placebo, followed by FOLFIRI. The primary end point was progression-free survival.. The intention-to-treat population comprised 332 patients. A clinical supply misallocation resulted in 198/332 (60%) patients receiving at least one cycle of misallocated treatment. Nevertheless, the addition of aflibercept to FOLFIRI was shown to improve progression-free survival (hazard ratio: 0.629; 95% CI: 0.488-0.812). Adverse events were in line with expectations.. The beneficial treatment effect associated with the addition of aflibercept to FOLFIRI was confirmed in Asian patients with pretreated metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retreatment; Treatment Outcome

This randomized phase III trial compared hepatic arterial infusion (HAI) chemotherapy with 5-fluorouracil (5-FU) followed by uracil/tegafur (UFT) and leucovorin (LV) versus UFT/LV alone for patients with curatively resected liver metastases from colorectal cancer (CRC).. The study was designed to include 280 patients to be randomized to receive either HAI with 5-FU followed by UFT/LV (Arm A) or UFT/LV alone (Arm B) to assess whether HAI chemotherapy improved disease-free survival (DFS).. Forty-four patients were randomized. Three-year DFS was relatively worse in the experimental arm although this difference was not statistically significant (43.5% in Arm A vs. 58% in Arm B; hazard ratio [HR], 1.304; P = 0.534). The experimental arm also tended to have a worse 3-year overall survival rate (80.2% in Arm A vs. 85.2% in Arm B; HR, 2.255; P = 0.192). There was no significant difference in the frequency of Grade 3 or higher toxicities between the two arms.. Although this study was limited by a small sample size after early study termination, our analysis found that HAI with 5-FU followed by UFT/LV did not improve the DFS of patients with curatively resected liver metastases from CRC compared with UFT/LV alone. The future studies are necessary to evaluate the survival benefit of HAI in combination with newer systemic chemotherapeutic agents for patients with resectable liver metastases from CRC.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Tegafur

BEVZ92 is a proposed biosimilar to bevacizumab. The two molecules have similar physicochemical and functional properties in in-vitro and preclinical studies. In this clinical study, we compared the pharmacokinetic profile, efficacy, safety, and immunogenicity of BEVZ92 with reference bevacizumab as a first-line treatment in patients with metastatic colorectal cancer.. We did a randomised, open-label trial at 15 centres in Argentina, Brazil, India, Spain, and Ukraine. Eligible patients were aged 18 years or older, had metastatic colorectal cancer with at least one measurable non-irradiated lesion for which first-line chemotherapy was indicated and Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, had not received previous treatment for advanced disease, and whose bone marrow, hepatic, renal, and coagulation markers were all within normal ranges. Patients were randomly assigned (1:1) to either BEVZ92 or reference bevacizumab (5 mg/kg on day 1 of each cycle every 2 weeks) in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or fluorouracil, leucovorin, and irinotecan (FOLFIRI). Randomisation was done via a web service based on a stochastic minimisation algorithm and was stratified by chemotherapy regimen (FOLFOX vs FOLFIRI), previous adjuvant therapy (yes vs no), ECOG performance status (0-1 vs 2), and study site. The primary endpoint was the area under the concentration-versus-time curve after a single infusion (AUC. 142 patients were randomly assigned, 71 to the BEVZ92 group and 71 to the reference bevacizumab group. Two participants assigned to BEVZ92 did not receive treatment (one withdrew consent, the other had a serious intestinal obstruction before starting treatment); therefore, the treated population comprised 69 patients in the BEVZ92 group and 71 in the reference bevacizumab group. The geometric mean ratio of AUC. Our results suggest that BEVZ92 and reference bevacizumab are pharmacokinetically bioequivalent and have no appreciable differences in efficacy, immunogenicity, and safety profiles as first-line treatment in combination with FOLFOX or FOLFIRI in patients with metastatic colorectal cancer.. mAbxience Research SL.

Topics: Adult; Aged; Antibodies; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bevacizumab; Biosimilar Pharmaceuticals; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Intention to Treat Analysis; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Progression-Free Survival; Therapeutic Equivalency

The most frequent bevacizumab-related side-effects are hypertension, proteinuria, bleeding and thromboembolism. To date, there is no biomarker that predicts anti-VEGF-associated toxicity. As autophagy inhibits angiogenesis, we hypothesised that single-nucleotide polymorphisms (SNPs) within autophagy-related genes may predict bevacizumab-mediated toxicity in patients with metastatic colorectal cancer (mCRC).. Patients with mCRC treated with first-line FOLFIRI and bevacizumab in two phase III randomised trials, namely the TRIBE trial (n = 219, discovery cohort) and the FIRE-3 trial (n = 234, validation cohort) were included in this study. Patients receiving treatment with FOLFIRI and cetuximab (FIRE-3, n = 204) served as a negative control. 12 SNPs in eight autophagy-related genes (ATG3/5/8/13, beclin 1, FIP200, unc-51-like kinase 1, UVRAG) were analysed by PCR-based direct sequencing.. The FIP200 rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grade 2-3 hypertension compared with the A/A genotype (3% versus 15%, odds ratio [OR] 0.17; 95% confidence interval [CI], 0.02-0.73; P = 0.009). Similarly, G allele carriers of the FIP200 rs1129660 SNP were less likely to develop grade 2-3 hypertension than patients with an A/A genotype in the FIRE-3 validation cohort (9% versus 20%, OR 0.43; 95% CI, 0.14-1.11; P = 0.077), whereas this association could not be observed in the control cohort (12% versus 9%, OR 1.40; 95% CI, 0.45-4.04; P = 0.60).. This is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Autophagy-Related Proteins; Bevacizumab; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Genotype; Humans; Hypertension; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Polymorphism, Single Nucleotide; Protein-Tyrosine Kinases

The Insulin-like growth factor (IGF)/IGF-receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF-1R SNPs in mCRC patients enrolled in the FIRE-3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and four SNPs of IGF1-IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct-sequencing in the FIRE-3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/- carriers (N= 105) achieved significantly worse OS compared to T/T (N = 464) in univariate (HR = 1.32 [95%CI 1.03-1.70], p = 0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/- variant (N= 280) achieved improved PFS compared to C/C (N = 257) in univariate (HR = 0.77 [95%CI 0.64-0.92], p = 0.004) and in multivariable. In the RAS wild-type subgroup IGF1 rs2946834 T/- carriers showed better PFS and OS compared to C/C (univariate HR for PFS = 0.65 [95%CI 0.51-0.81], p < 0.001; multivariable HR for PFS = 0.63 [95%CI 0.50-0.81], p < 0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild-type mCRC patient.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Genetic Association Studies; Humans; Insulin Receptor Substrate Proteins; Leucovorin; Male; Neoplasm Metastasis; Polymorphism, Single Nucleotide; Prognosis; Sequence Analysis, DNA; Signal Transduction; Somatomedins; Survival Analysis

The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis.. A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations.. Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy.. Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Disease-Free Survival; DNA Mutational Analysis; Female; Fluorouracil; GTP Phosphohydrolases; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Rectal Neoplasms; Survival Rate; Young Adult

The aim of this study was to assess the feasibility of a modified FOLFOX regimen as first-line treatment in elderly patients with metastatic gastric cancer (GC) or colorectal cancer (CRC).. We included chemotherapy-naïve patients over 80 years old with metastatic GC or CRC in our study. From September 2008 to November 2014, 28 consecutive patients were enrolled and treated with modified FOLFOX.. The study population consisted of an equal number of GC and CRC patients. The median age was 82.2 years in the GC group and 81.1 years in the CRC group. The total number of administered cycles was 89 (with a median of 6 per patient) in the GC group and 112 (with a median of 8 per patient) in the CRC group. Median progression-free survival (PFS) and overall survival (OS) were 5.4 and 6.6 months in the GC group and 7.3 and 8.1 months in the CRC group, respectively. There was no significant difference in PFS (p = 0.941) and OS (p = 0.238) between the GC and the CRC group. The 1-year survival rates were 35.7% with GC and 42.9% with CRC. Common grade 3/4 hematology toxicities were neutropenia (10.7%) and anemia (14.3%). Salvage chemotherapy was administered to 1 patient with GC and 7 patients with CRC.. The modified FOLFOX regimen can be cautiously considered as a first-line treatment option in extremely elderly patients with metastatic GC or CRC.

Topics: Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Feasibility Studies; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Republic of Korea; Stomach Neoplasms; Survival Rate; Treatment Outcome

Our aim was to explore the impact of the HER2/neu, HER3 receptor as well as their ligands' neuregulin (NRG1) expression on the outcome of patients with metastatic colorectal cancer (mCRC). NRG1, HER2/neu and HER3 expression was evaluated in 208 patients with mCRC receiving 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as the first-line treatment. Biomarker expression was correlated with the outcome of patients. NRG1 (low: 192 vs. high: 16), HER2/neu (low: 201 vs. high: 7) and HER3 (low: 69 vs. high: 139) expressions were assessed in 208 patients. High versus low NRG1 expression significantly affected progression-free survival (PFS) [4.7 vs. 8.2 months, hazard ratio (HR): 2.45; 95% confidence interval (CI): 1.45-4.13; P=0.001], but not overall survival (OS) (15.5 vs. 20.7 months, HR: 1.33; 95% CI: 0.76-2.35; P=0.32). High versus low HER3 expression (PFS: 7.1 vs. 8.8 months, HR: 1.11; 95% CI: 0.82-1.50; P=0.50; OS: 19.8 vs. 21.1 months, HR: 0.95; 95% CI: 0.70-1.30; P=0.75) and high compared with low HER2/neu expression (PFS: 7.7 vs. 8.0 months, HR: 1.07; 95% CI: 0.71-1.60; P=0.75; OS: 16.6 vs. 21.1 months, HR: 1.13; 95% CI: 0.75-1.71; P=0.57) did not influence outcome. High NRG1 expression was associated with inferior PFS in the FIRE-1 trial. We did not detect a prognostic impact of HER2/neu and HER3 overexpression in mCRC. The frequency of overexpression was comparable with other studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Neuregulin-1; Organoplatinum Compounds; Oxaliplatin; Prognosis; Receptor, ErbB-2; Receptor, ErbB-3; Retrospective Studies

Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients.. TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2.. The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases.. TRIBE2 is registered at Clinicaltrials.gov: NCT02339116 . January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Prospective Studies; Research Design; Treatment Outcome

We conducted an open-label single-arm phase II study by combining irinotecan (FOLFIRI) and bevacizumab (BV) plus erlotinib (ER) in 2nd-line chemotherapy for patients with metastatic colorectal cancer (mCRC).Eligible mCRC patients received 1st-line standard chemotherapy but still had progressive disease. They were given FOLFIRI plus BV at 2.5 mg/kg on day 1 per 2-week cycle, and daily 150 mg ER. The primary endpoint is progression-free survival (PFS).A total of 122 patients enrolled in the study. Among them, 55.7% were male patients and median age was 58.4 years (29-72 years). Median PFS was 7.1 months (95% CI 4.3-10.2). Median overall survival (OS) was 13.5 months (95% CI 9.7-16.4). No patients had complete responses, 24 patients had partial response (19.6%) and 59 had stable disease (48.4%). The most frequent adverse event (AE) was rash, with 66 patients (54.1%) had grade 3/4 rash. Other frequent grade 3/4 AEs were fatigue (n = 36, 29.5%), bleeding (n = 31, 25.4%), neutropenia (n = 23, 18.9%), and platelets (n = 14, 11.5%).Combining FOLFIRI and BV plus ER in 2nd-line chemotherapy is efficient to treat mCRC patients with acceptable safety.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Erlotinib Hydrochloride; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Retreatment; Treatment Outcome

A phase II study of S-1 plus leucovorin (LV) given in a 4-week schedule (2 weeks' administration followed by 2 weeks' rest) for patients with untreated metastatic colorectal cancer (mCRC) showed that the combination was effective, but grade 3 toxicities (diarrhea, stomatitis and anorexia) occurred at a relatively high rate. In this phase II study, we evaluated the efficacy and safety of a 2-week schedule of S-1 plus LV. Patients with mCRC received oral S-1 (40-60 mg) and LV (25 mg) twice daily for 1 week, followed by 1 week's rest. Treatment was repeated until disease progression or unacceptable toxicity. The primary endpoint was response rate. The pharmacokinetics of S-1 and LV in Chinese patients were evaluated on day 1 of the first cycle. Seventy-three patients were enrolled in Japan and China. Of 71 eligible patients, the response rate was 53.5%, and the disease control rate was 83.1%. Median progression-free survival and median overall survival were 6.5 and 24.3 months, respectively. The incidences of grade 3 toxicities were diarrhea 8.3%, stomatitis 8.3%, anorexia 2.8% and neutropenia 9.7%. There were no treatment-related deaths. The pharmacokinetics profiles of S-1 plus LV in Chinese patients were similar to those in Japanese patients. This 2-week schedule of S-1 plus LV showed good efficacy and better tolerability than the 4-week schedule. This therapy will be the base regimen for mCRC to be added by other cytotoxic or molecular-targeted drugs. The optimized treatment schedule for S-1 plus LV was 1 week on and 1 week off.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Combined Chemotherapy Protocols; China; Colorectal Neoplasms; Diarrhea; Drug Administration Schedule; Drug Combinations; Female; Humans; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Oxonic Acid; Stomatitis; Survival Analysis; Tegafur; Treatment Outcome

We explored the impacts of sequential application of various treatment lines on survival kinetics. Therefore, differences in overall survival (OS) observed in FIRE-3 were investigated in the context of time and exposure to applied treatment.. OS analyses (stratified by treatment with FOLFIRI plus either cetuximab or bevacizumab) were performed according to time intervals as well as using a Cox model to define changes of hazard ratio (HR) over time.. The fraction of patients with systemic treatment and time on treatment markedly decreases over treatment lines and time. OS evaluation by a Cox model indicated a trend towards a non-proportional hazard between treatment arms (P = 0.12/P = 0.09 for KRAS-intention-to-treat (ITT)/all-RAS wild-type populations, respectively). To improve the fit of the model, a change-point (point of curve separation) was estimated at 22.6 months (day 687) after randomisation. The HR between the two arms before 22.6 months was not significantly different from one. However, markedly different survival kinetics in favour of the cetuximab arm were apparent after the change-point (KRAS-ITT: P = 0.0018; HR, 0.60 [95% confidence interval [CI], 0.44-0.83] and RAS: P = 0.0006; HR, 0.51 [95% CI, 0.35-0.75]).. The differences in OS favouring the cetuximab arm become apparent about 22.6 months after randomisation, indicating that only those patients who survive 22.6 months after randomisation benefit from the superiority of the cetuximab arm. When OS curves separate, only few patients receive active systemic treatment in short courses, suggesting that earlier treatment effects are responsible for later kinetics of survival curves.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Leucovorin; Mutation; Neoplasm Metastasis; Proportional Hazards Models; Proto-Oncogene Proteins p21(ras); Risk Factors; Time Factors; Treatment Outcome

In patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC), outcomes with first-line chemotherapies are improved by adding weekly cetuximab. The APEC study investigated first-line once-every-2-weeks cetuximab plus chemotherapy for patients with KRAS wt mCRC; additional biomarker subgroups were also analyzed.. APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region. Patients (n = 289) received once-every-2-weeks cetuximab with investigator's choice of chemotherapy (FOLFOX or FOLFIRI). The primary end point was best confirmed overall response rate (BORR); progression-free survival (PFS) and overall survival (OS) were secondary end points. Early tumor shrinkage (ETS) and depth of response (DpR) were also evaluated.. In the KRAS wt population, BORR was 58.8%, median PFS 11.1 months, and median OS 26.8 months. Expanded RAS mutational analysis revealed that patients with RAS wt mCRC had better outcomes (BORR = 64.7%; median PFS = 13.0 months; median OS = 28.4 months). The data suggest that ETS and DpR may be associated with survival outcomes in the RAS wt population. Although this study was not designed to formally assess differences in outcome between treatment subgroups, efficacy results appeared similar for patients treated with FOLFOX and FOLFIRI. There were no new safety findings; in particular, grade 3/4 skin reactions were within clinical expectations.. The observed activity and safety profile is similar to that reported in prior first-line pivotal studies involving weekly cetuximab, suggesting once-every-2-weeks cetuximab is effective and tolerable as first-line therapy and may represent an alternative to weekly administration.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras); ras Proteins; Survival Rate

Cancer genomics and translational medicine rely on the molecular profiling of patient's tumor obtained during surgery or biopsy. Alternatively, blood is a less invasive source of tumor DNA shed, amongst other ways, as cell-free DNA (cfDNA). Highly-sensitive assays capable to detect cancer genetic events from patient's blood plasma became popularly known as liquid biopsy (LqB). Importantly, retrospective studies including small number of selected patients with metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapy have shown LqB capable to detect the acquired clonal mutations in RAS genes leading to therapy resistance. However, the usefulness of LqB in the real-life clinical monitoring of these patients still lack additional validation on controlled studies. In this context, we designed a prospective LqB clinical trial to monitor newly diagnosed KRAS wild-type (wt) mCRC patients who received a standard FOLFIRI-cetuximab regimen. We used BEAMing technique for evaluate cfDNA mutations in KRAS, NRAS, BRAF, and PIK3CA in twenty-five patients during a 2-y period. A total of 2,178 cfDNA mutation analyses were performed and we observed that: a) continued wt circulating status was correlated with a prolonged response; b) smoldering increases in mutant cfDNA were correlated with acquired resistance; while c) mutation upsurge/explosion anticipated a remarkable clinical deterioration. The current study provides evidences, obtained for the first time in an unbiased and prospective manner, that reinforces the utility of LqB for monitoring mCRC patients.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; DNA Mutational Analysis; Female; Fluorouracil; GTP Phosphohydrolases; Humans; Leucovorin; Liquid Biopsy; Male; Membrane Proteins; Neoplasm Metastasis; Prospective Studies; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Survival Analysis; Treatment Outcome

The optimal perioperative treatment for resectable esophageal squamous cell carcinoma (ESCC) remains controversial. We evaluated the efficacy and safety of leucovorin and 5-fluorouracil (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX) combination chemotherapies administered adjuvantly for curatively-resected, node-positive ESCC.. Patients with pathologically node-positive esophageal cancer after curative R0 resection were enrolled and randomly assigned to receive LV5FU2 or FOLFOX biweekly for up to eight cycles. The primary endpoint was disease-free survival (DFS).. Between 2011 and 2015, 62 patients were randomized into the two treatment groups (32 in the LV5FU2 arm and 30 in the FOLFOX arm). The median age was 60 years and both groups had similar pathologic characteristics in tumor, nodal status, and location. Treatment completion rates were similarly high in both groups. The DFS rate at 12 months was 67% in the LV5FU2 group and 63% in the FOLFOX group with a hazard ratio of 1.3 (95% confidence interval [CI], 0.66 to 2.62). After a median follow-up period of 27 months, the median DFS was 29.6 months (95% CI, 4.9 to 54.2) in the LV5FU2 arm and 16.8 months (95% CI, 7.5 to 26.1) in the FOLFOX arm (p=0.428), respectively, while the median overall survival was not reached in either arm. Grade 3 or 4 neutropenia was more frequent in patients in the FOLFOX arm than the LV5FU2 arm (20.0% vs. 3.1%).. The addition of oxaliplatin (FOLFOX) did not lead to better efficacy compared to LV5FU2 chemotherapy in an adjuvant setting in node-positive ESCC patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

Pegfilgrastim's role in reducing the risk of febrile neutropenia (FN) in patients with colorectal cancer (CRC) receiving chemotherapy plus bevacizumab was not previously evaluated in a prospective study. The present phase III, double-blind trial evaluated the efficacy of pegfilgrastim versus placebo in reducing the incidence of grade 3/4 FN in patients with advanced CRC receiving bevacizumab combined with first-line chemotherapy (FOLFOX [leucovorin, 5-fluorouracil, oxaliplatin] or FOLFIRI [leucovorin, 5-fluorouracil, irinotecan]).. Patients aged ≥ 18 years with locally advanced or metastatic CRC were randomized 1:1 to placebo or 6 mg of pegfilgrastim ∼24 hours after receiving chemotherapy plus bevacizumab every 14 days. The study treatment period included 4 cycles, but patients could continue treatment for ≤ 60 months. The primary endpoint was incidence of grade 3/4 FN in the first 4 cycles. The secondary endpoints included the objective response rate (ORR), overall survival, and progression-free survival, analyzed at the end of the long-term follow-up period.. A total of 845 patients were randomized from November 2009 to January 2012 (422, pegfilgrastim; 423, placebo). Pegfilgrastim significantly reduced the incidence of grade 3/4 FN in the first 4 treatment cycles (pegfilgrastim, 2.4%; 95% confidence interval [CI], 1.1%-4.3%; placebo, 5.7%; 95% CI, 3.7%-8.3%; odds ratio [OR], 0.41; P = .014). No significant differences were observed between the 2 arms in ORR (OR, 1.15; P = .330), overall survival (hazard ratio, 0.94; P = .440), and progression-free survival (hazard ratio, 0.93; P = .300).. Pegfilgrastim reduced the FN incidence in patients with advanced CRC receiving chemotherapy and bevacizumab. Administration of pegfilgrastim was tolerable and did not negatively affect the tumor response or survival in this patient population.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Febrile Neutropenia; Female; Filgrastim; Fluorouracil; Follow-Up Studies; Humans; Incidence; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Polyethylene Glycols; Proportional Hazards Models; Prospective Studies; Survival Rate; Vascular Endothelial Growth Factor A; Young Adult

Cetuximab-induced skin rash Gd3+ occurs in ≥16% patients (pts) (Heinemann et al., Lancet Oncol 15(10):1065-1075, 2014; Van Cutsem et al. J Clin Oncol 27(19):3117-25; 2009b). Survival, response, and toxicity parameters were re-evaluated under a pre-defined skin prophylaxis consistent of vitamin K1 ointment and oral doxycycline.. This is a national, multicenter, phase 4, first-line mCRC (K-RAS wt) trial. Pts received irinotecan 180 mg/m² (d1), FA 400 mg/m² (d1), 5-FU 400 mg/m² (d1), 5-FU 2400 mg/m² (d1-2), and cetuximab [400 mg/m² (d1), and then 250 mg/m² qw], prophylactic 0.1% vitamin K1 ointment qd, and oral doxycycline 100 mg bid.. 1-year PFS rate; secondary objectives: skin side-effects (grade, onset), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) time, and overall survival (OS) time and safety.. Twenty centers recruited 55 patients. Recruitment started Q1 2011 and ended Q3 2013 due to slow accrual. Characteristics were in line with CRYSTAL trial except for age and colonic location. 1-year PFS rate was 25.9%, mOS 21.8 months (m), and mPFS 8.5 m. ORR was 63.0%, DCR 77.8%. Rash Gd2+ occurred in 42.6% [median onset was 4.0 weeks (w)]; paronychia Gd2+ occurred in 22.2% (median onset 15.4w.); skin fissures Gd2+ occurred in 31.5% (median onset 19.9 weeks) 7% pts abandoned cetuximab treatment due to toxicity.. Our data reveal encouraging improvements in skin reactions and their time to occurrence due to a pre-defined skin care.

Topics: Adenocarcinoma; Administration, Cutaneous; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Chemoprevention; Colorectal Neoplasms; Doxycycline; Drug Eruptions; Exanthema; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Ointments; Skin Care; Treatment Outcome; Vitamin K 1

Dysregulated hepatocyte growth factor/mesenchymal-epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double-blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for mCRC (GO27827; NCT01418222).. Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg IV). Oxaliplatin was given for 8-12 cycles; other agents were continued until disease progression, unacceptable toxicity, or death. The primary endpoint was progression-free survival (PFS) in the intent-to-treat (ITT) and MET immunohistochemistry (IHC) expression-positive populations.. Between September 2011 and November 2012, 194 patients were enrolled. In September 2013, an interim analysis recommended stopping onartuzumab treatment due to lack of efficacy. At the time of the final analysis in February 2014, no significant improvement in PFS was seen with onartuzumab versus placebo in either the ITT or MET IHC-positive populations. An improvement in PFS was noted in the MET IHC-negative population. Neither overall survival nor response rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, and deep vein thrombosis was increased with onartuzumab relative to placebo.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Epithelial-Mesenchymal Transition; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

Fluorouracil and folinic acid with irinotecan (FOLFIRI) plus bevacizumab (BV) is widely used as second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, oxaliplatin, and BV. FOLFIRI requires a CV catheter and an infusion pump, which are inconvenient for patients. Sufficient data are not available for characterizing the effectiveness of fluoropyrimidines beyond first disease progression. In this study, we evaluated the efficacy and safety of irinotecan (CPT-11) plus BV as second-line therapy.. Thirty patients from six institutes were enrolled from March 2011 to January 2014. The median PFS was 5.7 months (95% CI 4.2-7.3 months), and the RR was 6.7% (range 0.8-22.1%). Grades 3-4 adverse events included leucopenia (36.7%), neutropenia (50%), thrombocytopenia (26.7%), anemia (30%), diarrhea (3.3%), anorexia (6.7%), and hypertension (3.3%). Relative dose intensities were 94.5 and 96.3% for CPT-11 and BV, respectively. The median OS was 11.8 months (6.3 months-not reached).. Administration of CPT-11 plus BV to patients with mCRC achieved comparable efficacies with relatively lower toxicities compared with the results of previous studies using FOLFIRI plus BV as second-line therapy. The dose intensity of CPT-11 was judged as satisfactory.. UMIN000005228.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Endpoint Determination; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

These negative phase II results for parsatuzumab highlight the challenges of developing an agent intended to enhance the efficacy of vascular endothelial growth factor inhibition without the benefit of validated pharmacodynamic biomarkers or strong predictive biomarker hypotheses.Any further clinical development of anti-EGFL7 is likely to require new mechanistic insights and biomarker development for antiangiogenic agents.. EGFL7 (epidermal growth factor-like domain 7) is a tumor-enriched vascular extracellular matrix protein that supports endothelial cell survival. This phase II trial evaluated the efficacy of parsatuzumab (also known as MEGF0444A), a humanized anti-EGFL7 IgG. One-hundred twenty-seven patients were randomly assigned to parsatuzumab, 400 mg, or placebo, in combination with mFOLFOX6 plus bevacizumab, 5 mg/kg. Treatment cycles were repeated every 2 weeks until disease progression or unacceptable toxicity for a maximum of 24 months, with the exception of oxaliplatin, which was administered for up to 8 cycles.. The progression-free survival (PFS) hazard ratio was 1.17 (95% confidence interval [CI], 0.71-1.93;. There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Calcium-Binding Proteins; Colorectal Neoplasms; Disease-Free Survival; EGF Family of Proteins; Endothelial Growth Factors; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

In Japan, oxaliplatin (OXA)/5-fluorouracil (5-FU)/leucovorin (LV)-the mFOLFOX6 regimen-is the most frequently used first-line chemotherapy backbone for metastatic colorectal cancer. However, peripheral nerve disorders caused by OXA during mFOLFOX6 therapy can decrease patients' quality of life. OXA can be safely discontinued from a FOLFOX regimen after 6 cycles during first-line therapy. Also, for patients who discontinue OXA without having experienced peripheral nerve disorders, reintroducing OXA in the later stages of treatment could remain an option.. The study is a phase II, multicenter, open-label, parallel-group, randomized, controlled exploratory study comparing the efficacy and safety of mFOLFOX6 plus panitumumab and 5-FU/LV plus panitumumab in patients with chemotherapy-naïve, unresectable, advanced or recurrent colorectal carcinoma of RAS wild-type (SAPPHIRE; ClinicalTrials.gov identifier, NCT02337946). Eligible patients will receive 6 cycles of mFOLFOX6 plus panitumumab combination therapy, followed by 1:1 randomization to either further treatment with mFOLFOX6 plus panitumumab or discontinuation of OXA and treatment with 5-FU/LV plus panitumumab. Up to 100 randomized patients will receive treatment for approximately 12 months or until any of the criteria for treatment discontinuation have been met. The primary endpoint is progression-free survival rate at 9 months after the day of randomization. The secondary endpoints are progression-free survival, overall survival, response rate, and interval to treatment failure. Safety will be evaluated according to the incidence and severity of adverse events, including the incidence of peripheral nerve and skin disorders. Additional endpoints will include maintenance of performance status, continuation of OXA in the mFOLFOX6 plus panitumumab group, and continuation of panitumumab in both groups.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Panitumumab; Quality of Life; Research Design; Survival Rate; Treatment Outcome

Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population.. We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506.. Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with fluorouracil and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]).. Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population.. Merrimack Pharmaceuticals.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Deoxycytidine; Diarrhea; Fatigue; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Pancreatic Neoplasms; Treatment Outcome; Vomiting

Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer. This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1, oxaliplatin, and leucovorin (SOL) in the treatment of Chinese patients with metastatic colorectal cancer (mCRC).. Eligible patients with untreated mCRC from four hospitals in China received intravenous oxaliplatin (85 mg/m(2)) on day 1, oral S-1 twice daily (80-120 mg per day) on day 1-7, and leucovorin twice daily (50 mg per day) simultaneously with S-1, every 2 weeks.. Forty patients were enrolled in our study. In total, 296 cycles of SOL were administered. The overall response rate was 50.0%. At a median follow-up of 27 months, progression-free survival and overall survival were 7.0 months (95% confidence interval [CI] 6.0-10.6 months) and 22.2 months (95% CI 15.1-29.3 months), respectively. The most common grade 3/4 non-hematological adverse events were diarrhea (n = 8, 20.0%), nausea (n = 3, 7.5%), and vomiting (n = 3, 7.5%). The most common grade 3/4 hematological toxicities were thrombocytopenia (n = 3, 7.5%), neutropenia (n = 1, 2.5%), and abnormal alanine transaminase/aspartate transaminase levels (n = 1, 2.5%). There was one treatment-related death.. The data indicate that the SOL regimen is effective and moderately tolerated in Chinese patients with mCRC.. ChiCTR-TNRC-100000838.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; China; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Survival Analysis; Tegafur; Treatment Outcome; Young Adult

This single-arm phase II study investigated the EGFR monoclonal antibody necitumumab plus modified FOLFOX6 (mFOLFOX6) in first-line treatment of locally advanced or metastatic colorectal cancer (mCRC).. Patients received 800-mg intravenous necitumumab (day 1; 2-week cycles), followed by oxaliplatin 85 mg m(-2), folinic acid 400 mg m(-2), and 5-fluorouracil (400 mg m(-2) bolus then 2400 mg m(-2) over 46 h). Radiographic evaluation was performed every 8 weeks until progression. Primary endpoint was objective response rate.. Forty-four patients were enrolled and treated. Objective response rate was 63.6% (95% confidence interval 47.8-77.6); complete response was observed in four patients; median duration of response was 10.0 months (7.0-16.0). Median overall survival (OS) and progression-free survival (PFS) were 22.5 (11.0-30.0) and 10.0 months (7.0-12.0), respectively. Clinical outcome was better in patients with KRAS exon 2 wild type (median OS 30.0 months (23.0-NA); median PFS 12.0 (8.0-20.0)), compared with KRAS exon 2 mutant tumours (median OS 7.0 months (5.0-37.0); median PFS 7.0 (4.0-18.0)). The most common grade ⩾3 adverse events were neutropenia (29.5%), asthenia (27.3%), and rash (20.5%).. First-line necitumumab+mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC; additional evaluation of the impact of tumour RAS mutation status is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proto-Oncogene Proteins p21(ras); Survival Analysis; Treatment Outcome

A multicenter, open-label, noncomparative, randomized phase II study (PEPCOL) was conducted to evaluate the efficacy and safety of the irinotecan or PEP02 (MM-398, nanoliposomal irinotecan) with leucovorin (LV)/5-fluorouracil (5-FU) combination as second-line treatment in patients with metastatic colorectal cancer (mCRC). Patients with unresectable mCRC who had failed one prior oxaliplatin-based first-line therapy were randomized toirinotecan with LV/5-FU (FOLFIRI) or PEP02 with LV/5-FU (FUPEP; PEP02 80 mg/m(2) with LV 400 mg/m(2) on day 1 and 5-FU 2400 mg/m(2) on days 1-2). Bevacizumab (5 mg/kg, biweekly) was allowed in both arms. The primary endpoint was 2-month response rate (RR). Fifty-five patients were randomized (FOLFIRI, n = 27; FUPEP, n = 28). In the intent-to-treat population (n = 55), 2-month RR response rate was observed in two (7.4%) and three (10.7%) patients in the FOLFIRI and FUPEP arms, respectively. The most common grade 3-4 adverse events reported in the respective FOLFIRI and FUPEP arms were diarrhea (33% vs. 21%), neutropenia (30% vs. 11%), mucositis (11% vs. 11%), and grade 2 alopecia (26% vs. 25%). FUPEP has activity and acceptable safety profile in oxaliplatin-pretreated mCRC patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Quality of Life; Retreatment; Sucrose; Treatment Outcome

Irinotecan is approved and widely administered to metastatic colorectal cancer (mCRC) patients; however, it can cause severe toxicities including neutropenia and diarrhea. The polymorphisms of genes encoding drug-metabolizing enzymes can play a crucial role in the increased susceptibility of cancer patients to chemotherapy toxicity. Therefore, we plan to explore the effect of the genetic polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) for irinotecan detoxification in mCRC patients. This trial will compare the clinical outcomes and side effects observed in mCRC patients treated with bevacizumab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with and without UGT1A1 genotyping and irinotecan dose escalation. A total of 400 mCRC patients were randomized into a study group and a control group.. This trial is a prospective, multicenter, randomized clinical trial comparing UGT1A1 promoter polymorphism for irinotecan dose escalation in mCRC patients administered with bevacizumab plus FOLFIRI as the first-line setting. The enrolled patients were randomly assigned to one of two groups, a study group and a control group, on the basis of receiving UGT1A1 genotyping or not. The study group receive a biweekly FOLFIRI regimen, with irinotecan dose escalation based on UGT1A1 genotyping; whereas the control group receive the conventional biweekly FOLFIRI regimen without UGT1A1 genotyping. The clinicopathological features, response rates, toxicity, and progression-free survival or overall survival will be compared between the two groups.. Patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan for a potentially more favorable clinical response and outcome, in addition to comparable toxicities. Such personalized medicine based on genotyping may be feasible for clinical practice.. NCT02256800 . Date of registration: 3 October 2014. Date of first patient randomized: 16 January 2015.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Fluorouracil; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Outcome Assessment, Health Care; Polymorphism, Genetic; Promoter Regions, Genetic; Prospective Studies

Low-dose radiation therapy (LDRT) can increase biological efficacy of chemotherapy. This Phase II trial evaluates LDRT plus FOLFIRI-bevacizumab (FOLFIRI-B) in metastatic colorectal cancer.. raising the clinical complete response rate from 5 to 25%.. toxicity, progression-free survival. Patients underwent 12 FOLFIRI-B cycles plus two daily LDRT fractions (20 cGy/6 h interval) on each cycle. Statistical analysis was planned on 18 patients.. Results on 18 patients are reported. Specifically considering irradiated sites: 15/18 patients had a partial (11/18) or complete (4/18) response. Among 11 partial responders, three became a pathological CR after surgery. Grade 3-4 toxicity was recorded in two patients (11.1%). At median follow-up of 30 months (range: 8-50), 7/18 patients progressed in irradiated sites.. Seven out of 18 patients (38.9%) had clinical or pathological CR in lesions treated with LDRT. Further studies on this newer treatment modality seem justified.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemoradiotherapy; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Radiotherapy Dosage; Treatment Outcome

FOLFOXIRI plus bevacizumab is a valid option as upfront treatment for metastatic colorectal cancer (mCRC) patients. While several trials investigated the effect of combining bevacizumab with different chemotherapy regimens, including fluoropyrimidines monotherapy and oxaliplatin- or irinotecan-containing doublets, no randomized comparison assessing the impact of the addition of bevacizumab to FOLFOXIRI is available.. A total of 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and 252 patients received first-line FOLFOXIRI plus bevacizumab in the TRIBE trial (FOLFOXIRI plus bevacizumab group). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the addition of bevacizumab to FOLFOXIRI in terms of survival and activity parameters.. Patients in the FOLFOXIRI group had more frequently Eastern Cooperative Oncology Group performance status of one or two, high Köhne score, metachronous and liver-limited disease, had previously received adjuvant treatments and had their primary tumors resected. The median progression-free survival (PFS) was 12.3 months in the FOLFOXIRI plus bevacizumab group compared with 10.0 months in the FOLFOXIRI group {propensity score-adjusted hazard ratio (HR) 0.74 [95% confidence interval (CI) 0.59-0.94], P = 0.013}. This association was significant also in the multivariable model (P = 0.024). The median OS was 29.8 months in the FOLFOXIRI plus bevacizumab group compared with 23.6 months in the FOLFOXIRI group [propensity score-adjusted HR: 0.72 (95% CI 0.56-0.93), P = 0.014]. At the multivariable model, the addition of bevacizumab was still associated with significantly longer OS (P = 0.030). No significant differences in RECIST response rate (RR) [65.1% versus 55.7%; propensity score-adjusted odds ratio (OR): 1.29 (95% CI 0.81-2.05), P = 0.280], early RR [62.7% versus 57.8%; OR: 1.14 (95% CI 0.68-1.93), P = 0.619] and median depth of response (42.2% versus 53.8%, P = 0.259) were reported.. Though in the absence of a randomized comparison, the addition of bevacizumab to FOLFOXIRI provides significant benefit in PFS and OS, thus supporting the use of FOLFOXIRI plus bevacizumab as upfront treatment for mCRC patients.. NCT01219920 and NCT00719797.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer.. Chemotherapy-naïve patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm.. Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade ≥ 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT.. The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liver-only metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression.. We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis.. Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056].. Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Italy; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Treatment Outcome

Irinotecan-based chemotherapy with bevacizumab is one of the first-line standard therapies for metastatic colorectal cancer (mCRC). TEGAFIRI (UFT/LV + irinotecan) is an irinotecan-based chemotherapy regimen. Currently, few clinical data regarding TEGAFIRI are available. This study evaluated the efficacy and safety of TEGAFIRI in Japanese patients with mCRC. This is a multicenter, randomized, phase II study. The major inclusion criteria were previously untreated patients with mCRC (age: 20-75 years, Eastern Cooperative Oncology Group performance status: 0-1). Eligible patients were randomly assigned (1:1) to receive either FOLFIRI ± bevacizumab or TEGAFIRI ± bevacizumab. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, dose intensity and toxicity. From November 2007 to October 2011, 36 and 35 patients assigned to the FOLFIRI and TEGAFIRI groups were included in the primary analysis. No significant difference in PFS was observed between the groups {median PFS: TEGAFIRI 9.9 months [95% confidence interval (CI), 6.5-14.7], FOLFIRI 10.6 months [95% CI, 7.7-16.5]; Hazard ratio, 0.98, 95% CI, 0.57-1.66, p = 0.930}. The response rates in the FOLFIRI and TEGAFIRI groups were 56% and 66%, respectively. Relative dose intensity was similar between the groups. The most common Grade 3/4 adverse event was diarrhea (26%) in TEGAFIRI group and neutropenia (39%) in the FOLFIRI group. The results of the present study indicate that TEGAFIRI ± bevacizumab is an effective and tolerable first-line treatment regimen for mCRC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Odds Ratio; Proportional Hazards Models; Recurrence; Tegafur; Treatment Failure; Treatment Outcome

The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC.. Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis.. Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%).. No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity.. NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab.. WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396.. Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months.. FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC.. UMIN000001396.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Japan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Proportional Hazards Models; Treatment Outcome

We previously showed that a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is not superior to FOLFOX4 in patients at advanced stage of colorectal cancer with liver metastases. Here we aimed to determine whether time to health-related quality of life (HRQoL) score definitive deterioration (TUDD) differs by study arm.. HRQoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 at baseline and every 4 cycles until the end of the study or death. Functional scale, symptom scale, global health status, and financial difficulties were analyzed. The TUDD was defined as the time interval between randomization and the first decrease in HRQoL score ≥ 5-point with no further improvement in HRQoL score ≥ 5 points or any further HRQoL data. TUDD was estimated using the Kaplan-Meier method and the long-rank test. Cox regression analyses were used to identify HRQoL items influencing TUDD. Sensitivity analyses were done using a multiple imputation method and different definitions of TUDD.. Of the 284 patients, 171 (60.2%) completed HRQoL questionnaires. Cox multivariate analysis showed no statistically significant difference in TUDD for most of the QLQ-C30 scales between treatments. Patients with dyspnea and those without symptoms at baseline had a significantly longer TUDD when there was a delay >12 months between diagnosis of the primary tumor and metastases (HR 0.48 [0.26-0.89]) and when there was diarrhea (HR 0.59 [0.36-0.96]), respectively.. This study shows that TUDD does not differ significantly according to type of treatment. The TUDD method produces meaningful longitudinal HRQoL results that may facilitate effective clinical decision making in patients with mCRC.. ClinicalTrials.gov NCT00268398.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Quality of Life; Treatment Outcome

The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ≥65 years), and time to progression (TTP) on first-line therapy (<6 versus ≥6 months).. OS and PFS were evaluated by the Kaplan-Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs.. Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ≥6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ≥65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (≥65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was similar across subgroups.. These analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC.. ClinicalTrials.gov, NCT01183780.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Proto-Oncogene Proteins p21(ras); Ramucirumab

FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes (KRAS and NRAS exons 2-4). We report here efficacy results for the FIRE-3 final RAS (KRAS/NRAS, exons 2-4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival.. FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov, number NCT00433927.. In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months [95% CI 24·5-39·4] vs 25·0 months [23·0-28·1]; hazard ratio 0·70 [0·54-0·90]; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% [95% CI 64·3-78·8] vs 97 of 173, 56·1% [48·3-63·6]; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% [60·3-75·4] vs 85 of 173, 49·1% [41·5-56·8]; p=0·0005), and median depth of response (-48·9% [-54·3 to -42·0] vs -32·3% [-38·2 to -29·2]; p<0·0001) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups.. This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup.. Merck KGaA and Pfizer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Response Evaluation Criteria in Solid Tumors; Tomography, X-Ray Computed

This randomized phase II trial compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab plus FOLFIRI as second-line chemotherapy for wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) and to explore the values of oncogenes in circulating tumor DNA (ctDNA) and serum proteins as predictive biomarkers. Patients with WT KRAS exon 2 mCRC refractory to first-line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI. Of 121 randomly assigned patients, 117 were eligible. Median overall survival (OS) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [hazard ratio (HR), 1.16; 95% CI, 0.76-1.77], respectively. Progression-free survival (PFS) was also similar (HR, 1.14; 95% CI, 0.78-1.66). KRAS, NRAS, and BRAF status using ctDNA was successfully examined in 109 patients, and mutations were identified in 19 patients (17.4%). Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations (P for interaction = 0.026 in OS and 0.054 in PFS). OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor-A (VEGF-A) levels and worse in those with low levels (P for interaction = 0.016). Second-line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Panitumumab; Proto-Oncogene Proteins B-raf; ras Proteins; Retreatment; Treatment Outcome

Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind VEGF receptors 1 and 2 (VEGFR-1 and -2), respectively. This randomized phase II study evaluated the antitumor activity and safety of icrucumab and ramucirumab each in combination with mFOLFOX-6 in patients with metastatic colorectal cancer after disease progression on first-line therapy with a fluoropyrimidine and irinotecan.. Eligible patients were randomly assigned to receive mFOLFOX-6 alone (mFOLFOX-6) or in combination with ramucirumab 8 mg/kg IV (RAM+mFOLFOX-6) or icrucumab 15 mg/kg IV (ICR+mFOLFOX-6) every 2 weeks. Randomization was stratified by prior bevacizumab therapy. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, safety, and PK.. In total, 158 patients were randomized, but only 153 received treatment (49 on mFOLFOX-6, 52 on RAM+mFOLFOX-6, and 52 on ICR+mFOLFOX-6). Median PFS was 18.4 weeks on mFOLFOX-6, 21.4 weeks on RAM+mFOLFOX-6, and 15.9 weeks on ICR+mFOLFOX-6 (RAM+mFOLFOX-6 versus mFOLFOX-6, stratified hazard ratio [HR] 1.116 [95% CI 0.713-1.745], P = 0.623; ICR+mFOLFOX-6 versus mFOLFOX-6, stratified HR 1.603 [95% CI 1.011-2.543], P = 0.044). Median survival was 53.6 weeks on mFOLFOX-6, 41.7 weeks on RAM+mFOLFOX-6, and 42.0 weeks on ICR+mFOLFOX-6. The most frequent adverse events reported on the ramucirumab arm (RAM+mFOLFOX-6) were fatigue, nausea, and peripheral sensory neuropathy; those on the icrucumab arm (ICR+mFOLFOX-6) were fatigue, diarrhea, and peripheral sensory neuropathy. Grade ≥3 serious adverse events occurred at comparable frequency across arms.. In this study population, combining ramucirumab or icrucumab with mFOLFOX-6 did not achieve the predetermined improvement in PFS.. NCT01111604.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Ramucirumab

Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate.. The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n=612) or placebo (n=614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0.. The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept- and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months. The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy- and anti-vascular epithelial growth factor (VEGF)-associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence.. The addition of aflibercept to FOLFIRI showed a continued and persistent improvement in overall survival over time in patients with mCRC. Although grade 3-4 AEs were more frequent in the aflibercept arm, they occurred in early treatment cycles and decreased sharply following initial presentation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Camptothecin; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

Biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) enhances antitumor activity. LV is thus often added to 5-FU-based regimens for the treatment of metastatic colorectal cancer (mCRC). A combination of S-1, oxaliplatin, and LV (SOL) was shown to be feasible, effective, and safe in a previous phase I trial. We therefore conducted a randomized phase II trial to evaluate efficacy and safety of SOL compared with mFOLFOX6.. Patients with mCRC and no prior chemotherapy were randomly assigned to receive either SOL or mFOLFOX6. SOL consisted of S-1 (40-60 mg bid) plus oral LV (25 mg bid) for 1 week and oxaliplatin (85 mg/m(2)) on day 1, repeated every 2 weeks.. Among 107 patients enrolled from July 2008 through July 2009, 105 (56 in the SOL group and 49 in the mFOLFOX6 group) were eligible and evaluated. The median progression-free survival was 9.6 months in the SOL group and 6.9 months in the mFOLFOX6 group [hazard ratio (HR) 0.83, 95 % confidence interval (CI) 0.49-1.40]. The median overall survival was 29.9 and 25.9 months, respectively (HR 0.91, 95 % CI 0.55-1.49). The response rate was 55 % in both groups. Grade 3 or 4 adverse drug reactions were neutropenia (20 % with SOL vs 41 % with mFOLFOX6), sensory neuropathy (20 vs 2.0 %), anorexia (13 vs 7.8 %), fatigue (11 vs 5.9 %), and diarrhea (11 vs 3.9 %).. SOL demonstrated promising efficacy and acceptable toxicity as first-line chemotherapy for mCRC. Further studies of SOL combined with molecular target agents are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Survival Rate; Tegafur; Treatment Outcome

The immune modulatory oligonucleotide IMO-2055 (EMD 1201081) is a phosphorothioate oligodeoxynucleotide agonist of Toll-like receptor 9. In preclinical studies, IMO-2055 was shown to activate natural killer cells and to support the antitumor activity of monoclonal antibodies. This phase 1b, open-label, 3 + 3 dose-escalation trial was performed to determine the recommended phase 2 dose of IMO-2055 combined with FOLFIRI/cetuximab in patients with previously treated, advanced/metastatic colorectal cancer (NCT00719199).. Patients received 14-day cycles of cetuximab (days 1/8; 400 mg/m(2) day 1 cycle 1, 250 mg/m(2) for subsequent days/cycles), irinotecan (day 1; 180 mg/m(2)), folinic acid (day 1; 400 mg/m(2) racemic or 200 mg/m(2) L-form), 5-fluorouracil (day 1; 400 mg/m(2) intravenous bolus, followed by 2,400 mg/m(2) as 46-h infusion), and escalating IMO-2055 doses (days 1/8; 0.16, 0.32, 0.48 mg/kg). Fifteen patients received IMO-2055, including six, three, and six patients who were treated at the dose levels 0.16, 0.32, and 0.48 mg/kg, respectively.. One dose-limiting toxicity was observed (grade 3 fatigue; at dose level 0.16 mg/kg). The most common adverse events were injection site reactions, diarrhea, fatigue, hypomagnesemia, and stomatitis. One patient achieved a confirmed partial response; 12 had stable disease, including five with stable disease ≥4.0 months.. IMO-2055 combined with FOLFIRI/cetuximab was well tolerated at all dose levels tested. IMO-2055 0.48 mg/kg was considered as the recommended phase 2 dose.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Oligonucleotides; Toll-Like Receptor 9

This study was conducted to evaluate the efficacy and safety of the combination of capecitabine and oral leucovorin (LV) as a third-line chemotherapy for patients with metastatic colorectal cancer (CRC) showing resistance to irinotecan- and oxaliplatin-containing regimens.. Patients who showed disease progression while receiving or within 6 months of discontinuing irinotecan- and oxaliplatin-containing regimens received capecitabine 825 mg/m(2) in combination with oral LV at a fixed dose of 30 mg, twice a day for 2 weeks followed by a 1-week rest.. Twenty-five patients were enrolled from July 2011 to June 2014. Three patients achieved PR, and 11 showed SD. The overall response rate was 12 %, and disease control rate was 56 %. With a median follow-up of 6.8 months, the median time to progression was 2.8 months and the median overall survival was 7.1 months. The most common non-hematologic toxicity was hand-foot syndrome (40 %), followed by mucositis (28 %) and diarrhea (12 %). Grade 3 hand-foot syndrome occurred in two patients (8 %), and grade 3 mucositis in one. Hematologic toxicities were mild, and only one patient developed grade 3 thrombocytopenia.. The combination of capecitabine and oral LV showed a modest activity and tolerable toxicity profile in metastatic CRC patients pretreated with irinotecan- and oxaliplatin-containing regimens. Oral LV seems to be able to reduce the usual dose of capecitabine when the two drugs are combined.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Treatment Outcome

We conducted a phase II trial of 5-fluorouracil and oxaliplatin combination chemotherapy as a second-line treatment in unresectable/metastatic biliary tract cancer patients who had failed gemcitabine-based chemotherapy.. Patients treated with gemcitabine-based palliative treatment were enrolled in this study. Patients were received modified FOLFOX3 (mFOLFOX3) consists of oxaliplatin 85 mg/m(2) (day 1) and leucovorin 30 mg (days 1, 2) followed by 5-fluorouracil 1,500 mg/m(2) (days 1, 2) every 2 weeks.. Between March 2010 and June 2012, a total of 30 patients were enrolled in this study. Twenty-eight patients were measurable for treatment response. One achieved complete response, and one a partial response was observed. Overall response rate was 7.1% (95% confidence interval 0.9-23.5%). The median progression-free survival was 1.6 months, and the median overall survival was 4.4 months. Grade 3-4 hematologic toxicities included neutropenia (6.7%) and thrombocytopenia (3.4%). The most common non-hematologic toxicity was neuropathy (22.2%). However, the most common grade 3-4 non-hematologic toxicity was hyperbilirubinemia (5.0%). There was one treatment-related death due to neutropenic infection.. mFOLFOX3 as a second-line regimen has modest effect and tolerable toxicity in unresectable/metastatic biliary tract cancer patients who have been treated previously via gemcitabine-based chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Treatment Failure

Early tumor shrinkage (ETS) and depth of response (DoR) predict overall survival (OS) in first-line trials of chemotherapy ± anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC). These associations and the predictive accuracy of response measurements for survival parameters were investigated in the phase III TRIBE trial of FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev.. A landmark approach was adopted to define the assessable population. The distribution of RECIST response rate, ETS and DoR was compared in the two arms. Associations between response measurements and progression-free survival (PFS), post-progression survival (PPS) and OS were tested by univariate and multivariate Cox models. Prediction performance of each factor was estimated by C-index.. A significantly higher percentage of patients in the FOLFOXIRI plus bev arm achieved ETS ≥20%, when compared with the control arm (62.7% versus 51.9%, P = 0.025). Also the DoR was significantly higher in the triplet plus bev arm (43.4% versus 37.8%, P = 0.003). Both ETS and DoR were associated with PFS, PPS and OS at the univariate analyses and in the multivariate models stratified for other prognostic variables. Both ETS and DoR were able to predict survival as accurately as RECIST response.. FOLFOXIRI plus bev improves ETS and DoR when compared with FOLFIRI plus bev. Achieving rapid and deep tumor shrinkage consistently delays tumor progression and prolongs survival in patients treated with first-line chemotherapy plus bev. ETS is a promising and valuable end point for clinical trials' design deserving further investigation.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chi-Square Distribution; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Fluorouracil; Humans; Italy; Kaplan-Meier Estimate; Leucovorin; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Organoplatinum Compounds; Proportional Hazards Models; Risk Factors; Time Factors; Treatment Outcome; Tumor Burden

We report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT).. mCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups.. Between November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2-10.3] and 8.4 (95% CI 7.2-9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70-1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia.. The addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population.. NCT01878422.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Humans; Italy; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Proportional Hazards Models; Risk Factors; Time Factors; Treatment Outcome

The oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC.. In this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4-10 and 18-24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety.. Median overall treatment duration with any study drug was 9.9 months (range 0.6-19.6); median treatment duration with regorafenib was 7.7 months (range 0.1-19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications.. Regorafenib+mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Historically Controlled Study; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Phenylurea Compounds; Pyridines; Treatment Outcome

Retrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression.. Originally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS).. A total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab.. Although prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Prognosis; Prospective Studies; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase

Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.. Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01183780.ld. We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4-14·5) for patients in the ramucirumab group versus 11·7 months (10·8-12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730-0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 [38%] of 529 patients in the ramucirumab group vs 123 [23%] of 528 in the placebo group, with febrile neutropenia incidence of 18 [3%] vs 13 [2%]), hypertension (59 [11%] vs 15 [3%]), diarrhoea (57 [11%] vs 51 [10%]), and fatigue (61 [12%] vs 41 [8%]).. Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable.. Eli Lilly.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Ramucirumab

A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy.. Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety.. Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups.. Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment.. UMIN000002557.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Salvage Therapy; Survival Rate

In the NORDIC-7.5 trial, how cetuximab might safely and conveniently be added to an intermittent treatment strategy in patients with prospectively selected Kirsten rat sarcoma viral oncogene homolog wild type (KRASwt) metastatic colorectal cancer (mCRC) was investigated. Patients were treated in a multicenter phase II trial with cetuximab in combination with the Nordic bolus FLOX (oxaliplatin, 5-fluorouracil, and folinic acid) for 4 months followed by maintenance cetuximab.. Patients had KRASwt, nonresectable mCRC, no previous chemotherapy, and Eastern Cooperative Group performance status of 0 to 2. Patients received 8 courses of Nordic FLOX (oxaliplatin 85 mg/m(2) over 1 hour on day 1, and 5-fluorouracil 500 mg/m(2) as a bolus injection, followed 30 minutes later with bolus folinic acid 60 mg/m(2) on days 1 and 2). Cetuximab was administered every 2 weeks at a dose of 500 mg/m(2) for 16 weeks followed by cetuximab as maintenance therapy until disease progression.. Between July 2008 and September 2010, 152 KRASwt patients were included. The response rate was 62% (95% confidence interval [CI], 54%-69%), median progression-free survival was 8.0 months (95% CI, 7.5-8.9) and median overall survival was 23.2 (95% CI, 18.1-27.4) months. Twenty-one patients (14%) had later R0-resection of metastasis. FLOX with cetuximab was reintroduced in 47 of 85 patients (55%). The most common Grade 3/4 nonhematologic adverse events were diarrhea in 14 patients (9%), skin rash in 13 patients (9%), infection without neutropenia in 11 patients (7%), and fatigue in 11 patients (7%).. In a prospectively selected KRASwt population, biweekly cetuximab was safely integrated in an intermittent chemotherapy strategy and might have added to a longer chemotherapy-free interval. However, the combination of biweekly cetuximab with chemotherapy needs to be validated in trials using FOLFOX (oxaliplatin, fluorouracil, and leucovorin) or FOLFIRI (irinotecan, fluorouracil, and leucovorin).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Proto-Oncogene Proteins p21(ras); Treatment Outcome

Tumour shrinkage (TS) increases the possibility of resection in metastatic colorectal cancer (mCRC) and may improve tumour-related symptoms. Here we report prespecified secondary response-related end-points and exploratory TS/resection outcomes for patients with RAS wild-type (WT) tumours (no mutations in KRAS/NRAS exons 2/3/4) from the PRIME study (NCT00364013).. PRIME was a randomised phase 3 study comparing first-line panitumumab+FOLFOX4 versus FOLFOX4 in mCRC patients. Tumour response analyses were conducted to compare response rates and their impact on survival outcomes.. Overall, 505 patients had RAS WT mCRC. More patients receiving panitumumab+FOLFOX4 versus FOLFOX4 had ⩾30% (59% versus 38%; P<0.001) or ⩾20% (72% versus 57%; P<0.001) TS at week 8 (early TS); consistent TS benefits were observed over the first ∼40weeks of treatment. Objective response rate (P=0.003), duration of response (P=0.0027), depth of response (P=0.0149), progression-free survival (PFS; P=0.0015) and overall survival (OS; P=0.0057) were improved in the panitumumab+FOLFOX4 group. Both early TS and resection were associated with improved PFS and OS. 2-year OS rates for patients who did (n=64) versus did not (n=441) undergo resection were 88% versus 40%; 2-year OS rates for patients who did (n=45) versus did not (n=460) undergo complete resection were 96% versus 41%.. More patients receiving panitumumab+FOLFOX4 versus FOLFOX4 had ⩾30% or ⩾20% TS at week 8; PFS and OS were also improved with panitumumab+FOLFOX4. The clinical value of achieving early TS in mCRC warrants further investigation.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Treatment Outcome

The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPK-targeted agents such as pimasertib.. Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. The primary objective of the safety run-in phase was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose of pimasertib combined with FOLFIRI.. Sixteen patients were enrolled in the trial. Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI, respectively. The MTD was considered to be 45 mg per day. The most common treatment-emergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated.. Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45 mg per day, pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns were identified.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Niacinamide; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome

Bevacizumab combined with modified FOLFOX6 is a standard regimen for colorectal cancer. The present study was to determine the efficacy and safety of bevacizumab-modified FOLFOX6 regimen in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2/neu)-negative MBC.. Bevacizumab, 5 mg/kg every two weeks or 7.5 mg/kg every three weeks, was administered with modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 on day 1, followed by 5-FU 2400 mg/m2 intravenous infusion over 46 hours every 2 weeks) to patients who failed at least 1 chemotherapy regimen in the metastatic setting. The primary objective was progression free survival (PFS). Secondary objectives included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), safety, and the change of tumor size and Eastern Cooperative Oncology Group (ECOG) performance status.. 69 patients were enrolled. The median PFS was 6.8 months (95% CI, 5.0 to 8.5 months), ORR was 50.0% and median OS was 10.5 months (95% CI, 7.9 to 13.1 months). Patients showing objective responses had a 4.2-month median PFS gain and 5.7-month median OS gain compared with those who did not (P < 0.05). Grade 3 or 4 adverse events occurring in more than one patient were neutropenia (53/69, 76.8%), leukopenia (36/69, 52.2%), thrombocytopenia (13/69, 18.8%), anemia (3/69, 4.3%) and hypertension (3/69, 4.3%).. Adding bevacizumab to modified FOLFOX6 does have significant anti-tumor activity and good safety profile in heavily pretreated HER2/neu-negative MBC patients. Further trials are required to confirm whether the high ORR can translate into a long-term PFS and even OS benefit.. www.clinicaltrials.gov NCT01658033.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Receptor, ErbB-2; Retreatment; Treatment Outcome

Adding leucovorin to fluorouracil is known to improve response rate and overall survival in first-line chemotherapy for metastatic colorectal cancer (mCRC). The present multicenter phase II study evaluated the efficacy and safety of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA).. Patients with unresectable and untreated mCRC received S-1 (40-60 mg bid) plus leucovorin (25 mg bid) orally for 1 week, and oxaliplatin (85 mg/m(2)) and bevacizumab (5 mg/kg) intravenously on day 1, every 2 weeks. Efficacy endpoints, including the response rate (the primary endpoint) and progression-free survival, were assessed by an independent review committee.. Of the 29 eligible patients, 25 patients (86%) had a partial response [95% confidence interval (CI) 68-96%] and the remaining four patients showed stable disease with a trend toward tumor shrinkage. The median progression-free survival was 15 months (95% CI 10-26 months). The median overall survival was not reached after a median follow-up time of 34 months. The 3-year survival rate was 54%. Curative resections of metastatic lesions were performed in eight patients (28%). Common grade 3 or 4 adverse events were neutropenia (20%), hypertension (23%), anorexia (20%), fatigue (17%), diarrhea (10%), and peripheral sensory neuropathy (53%).. The SOLA therapy showed excellent efficacy and tolerable toxicities except for peripheral sensory neuropathy in patients with mCRC. Since oxaliplatin-induced neuropathy can be alleviated by modifying its administration, SOLA is a promising candidate regimen to be compared with FOLFOX plus bevacizumab in a future phase III trial.. JapicCTI-090881.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

S-1, a novel oral prodrug of 5-fluorouracil (5-FU), and irinotecan with or without bevacizumab is known to be effective in metastatic colorectal cancer (mCRC). However, it is not clear whether S-1 and irinotecan confers benefits compared to 5-FU and leucovorin plus oxaliplatin (FOLFOX) in patients with mCRC. Our aim was to compare the efficacy and safety of these regimens.. We analyzed 187 patients with previously untreated mCRC who were enrolled in four phase II studies: SIR (S-1 and irinotecan, n = 40), SIRB (S-1 and irinotecan with bevacizumab, n = 51), FOLFOX (5-FU and leucovorin plus oxaliplatin, n = 46), and STOX (stop-and-go strategy of modified FOLFOX-6 with bevacizumab, n = 50). We evaluated efficacy and safety between SIR/SIRB and FOLFOX/STOX.. Baseline characteristics were similar in the two groups composed of SIR/SIRB (n = 91) and FOLFOX/STOX (n = 96). The overall response rates were not significantly different between the two groups (65% in SIR/SIRB vs. 52% in FOLFOX/STOX, p = 0.125). The median progression-free survival was 10.9 months in SIR/SIRB versus 12.1 months in FOLFOX/STOX (p = 0.59). The median overall survival was 27.3 months in SIR/SIRB versus 26.8 months in FOLFOX/STOX (p = 0.97). Gastrointestinal adverse events were the most common toxicities in SIR/SIRB, while neutropenia and sensory neuropathy were the most common toxicities in FOLFOX/STOX.. S-1 and irinotecan with or without bevacizumab was well tolerated and showed similar response rates and survival compared to the FOLFOX regimen. This combination should be considered as an experimental first-line treatment for mCRC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Treatment Outcome

This randomised, open-label, phase I/II study evaluated the efficacy and safety of nintedanib, an oral, triple angiokinase inhibitor, combined with chemotherapy, relative to bevacizumab plus chemotherapy as first-line therapy in patients with metastatic colorectal cancer (mCRC).. Patients with histologically confirmed mCRC (adenocarcinoma), an Eastern Cooperative Oncology Group performance status ≤ 2 and adequate organ function were included. Patients were randomised 2:1 to receive nintedanib 150 mg or 200 mg b.i.d. plus mFOLFOX6 (oxaliplatin 85 mg/m(2), l-leucovorin 200 mg/m(2) or d,l-leucovorin 400 mg/m(2), 5-fluoruracil bolus 400 mg/m(2) followed by 2400 mg/m(2), every 2 weeks) or bevacizumab (5 mg/kg every 2 weeks) plus mFOLFOX6. During phase I, patients underwent a 3 + 3 dose-escalation schema to determine the maximum tolerated dose (MTD) of nintedanib in combination with mFOLFOX6. The primary end point was progression-free survival (PFS) rate at 9 months. Objective response (OR) was a secondary end point.. The nintedanib recommended phase II dose was 200 mg b.i.d. plus mFOLFOX6 based on safety data from phase I (n = 12). Of 128 patients randomised in the phase II part, 126 received treatment (nintedanib plus mFOLFOX6, n = 85; bevacizumab plus mFOLFOX6, n = 41). PFS at 9 months was 62.1% with nintedanib and 70.2% with bevacizumab [difference: -8.1% (95% confidence interval -27.8 to 11.5)]. Confirmed ORs were recorded in 63.5% and 56.1% of patients in the nintedanib and bevacizumab groups, respectively. The incidence of adverse events (AEs) considered related to treatment was 98.8% with nintedanib and 97.6% with bevacizumab; the incidence of serious AEs was 37.6% with nintedanib and 53.7% with bevacizumab. The pharmacokinetics of nintedanib and the components of mFOLFOX6 were unaffected by their combination.. Nintedanib in combination with mFOLFOX6 showed efficacy as first-line therapy in patients with mCRC with a manageable safety profile and further studies in this population are warranted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Indoles; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate

The mean 5-6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy.. Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0-2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80-120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR).. A total of 31 patients were enrolled. DCR was 65% [95% confidence interval (CI), 48-100%] and the response rate was 7% (95% CI, 0.7-22%). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95% CI, 2.1-9.3] and 9.9 [95% CI, 7.4-NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26%) and diarrhea (11%), which were manageable by dose reduction/interruption.. SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC.. This study has been registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( ID UMIN000009083 ) on 11 October 2012.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Salvage Therapy; Tegafur; Treatment Outcome

In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival-a secondary endpoint-and report treatment efficacy in RAS and BRAF molecular subgroups.. TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m(2) intravenous infusion of irinotecan for 60 min followed by a 200 mg/m(2) intravenous infusion of leucovorin for 120 min, a 400 mg/m(2) intravenous bolus of fluorouracil, and a 2400 mg/m(2) continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m(2) intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m(2) intravenous infusion of oxaliplatin given concurrently with 200 mg/m(2) leucovorin for 120 min, followed by a 3200 mg/m(2) continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014. The trial is registered with ClinicalTrials.gov, number NCT00719797.. Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7-55·6), median overall survival was 29·8 months (95% CI 26·0-34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5-29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65-0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7-42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4-28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11-1·99) and 13·4 months (8·2-24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75-4·46; likelihood-ratio test p<0·0001). Treatment effect was not significantly different across molecular subgroups (pinteraction=0·52).. FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study, irrespective of baseline clinical characteristics and RAS or BRAF mutational status.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; DNA Mutational Analysis; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Intention to Treat Analysis; Irinotecan; Italy; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Time Factors; Treatment Outcome

We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective-retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183).. Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints.. The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54-0.91); P = 0.007 vs. 0.73 (95% CI, 0.59-0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63-1.03); P = 0.08 vs. 0.85 (95% CI, 0.70-1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab-FOLFIRI group versus 10% in the FOLFIRI group.. Patients with RAS mutations were unlikely to benefit from panitumumab-FOLFIRI and the benefit-risk of panitumumab-FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469-79. ©2015 AACR.See related commentary by Salazar and Ciardiello, p. 5415.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; DNA Mutational Analysis; Exons; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Panitumumab; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Retreatment; Survival Analysis; Treatment Outcome

Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC.. Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs).. Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs.. This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; Female; Fluorouracil; Humans; Interleukin-8; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Survival Analysis; Treatment Outcome; Vascular Endothelial Growth Factor B

The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab.. In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00973609.. Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5-25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1-8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3-7·4) for the bevacizumab alone group, and 6·4 months (4·8-7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 1·08 [95% CI 0·85-1·37]; p=0·53; upper limit of the one-sided 99·8% CI 1·42), whereas no treatment was not (HR 1·26 [0·99-1·60]; p=0·056; upper limit of the one-sided 99·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 [19%] patients in the fluoropyrimidine plus bevacizumab group, 67 [43%] in the bevacizumab monotherapy group, and 73 [46%] in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 [13%] of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 [14%] of 156 patients in the bevacizumab alone group, and 12 [8%] of 158 patients in the no treatment group).. Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Disease Progression; Drug Substitution; Female; Fluorouracil; Germany; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Risk Factors; Time Factors; Treatment Failure

Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC.. AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m(2)) plus gemcitabine (1000 mg/m(2)) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m(2)) plus sLV5FU2 (leucovorin 400 mg/m(2) followed by bolus 400 mg/m(2) 5-fluorouracil and by 5-fluorouracil 2400 mg/m(2) as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed.. The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC.. AFUGEM is registered at Clinicaltrials.gov: NCT01964534 , October 15, 2013.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Clinical Protocols; Deoxycytidine; Equilibrative Nucleoside Transporter 1; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Neoplasm Metastasis; Paclitaxel; Pancreatic Neoplasms; Translational Research, Biomedical

The clinical benefit of cetuximab combined with oxaliplatin-based chemotherapy remains under debate. The aim of the present multicenter open-label Phase II study was to explore the efficacy and safety of biweekly administration of cetuximab and mFOLFOX-6 or XELOX as first-line chemotherapy in patients with metastatic colorectal cancer.. Sixty-two patients with previously untreated KRAS/BRAF wild-type metastatic colorectal cancer were recruited to the study between April 2010 and May 2011. Patients received one of two treatment regimens, either cetuximab plus mFOLFOX-6 (FOLFOX + Cmab) or cetuximab plus biweekly XELOX (XELOX + Cmab), according to their own preference. Treatment was continued until disease progression or the appearance of intolerable toxicities. The primary endpoint was response rate; secondary endpoints were progression-free survival, overall survival, disease control rate, dose intensity, conversion rate to surgical resection, and safety.. The response rates in the FOLFOX + Cmab (n = 37) and XELOX + Cmab (n = 25) groups were 64.9 % (24/37) and 72.0 % (18/25), respectively. The median PFS in the FOLFOX + Cmab and XELOX + Cmab groups was 13.1 months (95 % confidence interval [CI] 12.1-17.5) and 13.4 months (95 % CI 10.1-17.9), respectively. Neutropenia was the most frequent grade 3/4 adverse event in both groups (33.9 %), followed by anorexia, acneiform eruption, skin fissure and paronychia. A waterfall plot of tumor diameter showed prominent shrinkage of the tumors in 88.7 % of patients.. The results of the present study indicate that biweekly cetuximab plus mFOLFOX-6/XELOX is an effective and tolerable treatment regimen. Biweekly administration of cetuximab requires only one hospital visit every 2 weeks, and may become a convenient treatment option for patients with KRAS/BRAF wild-type metastatic colorectal cancer.. This study is registered with University Hospital Medical Information Network (UMIN 000003253 ). Registration date is 02/24/2010.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cetuximab; Colorectal Neoplasms; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Oxaloacetates; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Treatment Outcome

High-dose FOLFIRI has an acceptable safety profile and promising efficacy. UDP-glucuronosyltransferase: (UGT1A1) polymorphism may be predictive of toxicity and efficacy of irinotecan. This phase II study aimed to evaluate the combination of high-dose FOLFIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer (MCRC) based on their UGT1A1 genotype. Patients with the UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotype received bevacizumab plus high-dose FOLFIRI every 2 weeks. Using the Bryant and Day design with objective response rate and toxicity as the primary endpoints, 54 patients in each group were required with a planned interim analysis after inclusion of 17 patients per group. We planned to stop the trial at the interim analysis if ≤ 7 patients exhibited an objective response (OR) and/or ≥ 3 patients exhibited severe toxicity. At the interim analysis, ORs were higher than the number expected: 52.9% (group 1) and 58.8% (group 2). More than three toxic events occurred in both groups and, according to the interim analysis rule, the trial was closed due to unacceptable toxicity. Recruitment was stopped when 86 patients were included and an analysis on overall population was done for overall survival (OS) and progression-free survival (PFS). The median PFS was 10.7 months (group 1) and 10.4 months (group 2). The median OS was 25.5 months (group 1) and 23.9 months (group 2). This trial does not support the use of the intensive treatment with HD-FOLFIRI plus bevacizumab combination for MCRC in patients with the UGTA1*1/UGT1A1*1 or UGT1A1*1/UGT1A1*28 genotype.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Polymorphism, Genetic

The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer.. We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1:1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m(-2) as a 90-min infusion, leucovorin at 200 mg m(-2) as a 2-h infusion, and a bolus injection of 5-FU 400 mg m(-2) followed by a 46-h continuous infusion of 5-FU at 2400 mg m(-2). The XELIRI regimen consisted of irinotecan at 250 mg m(-2) as a 90-min infusion with capecitabine 1000 mg m(-2) twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity.. Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5-7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4-8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively).. The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colorectal Neoplasms; Double-Blind Method; Drug Administration Schedule; Female; Fluorouracil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Republic of Korea; Simvastatin; Survival Analysis; Treatment Outcome

The efficacy of a cetuximab-based regimen used to treat metastatic colorectal cancer (mCRC) could be influenced by VEGFA polymorphisms.. We studied the effects of five polymorphisms in the VEGFA gene (-2549D/I, -1154G/A, -460T/C, +405G/C and +936C/T) on the outcome of 98 mCRC patients treated with FOLFIRI plus cetuximab.. Patients homozygous for the -2549D, -1154G and -460T alleles did exhibit higher response rates to treatment and longer progression-free survival compared with others. In addition, the DGTGC and IGCGC haplotypes were significantly associated with a lower risk of disease progression.. These findings suggest that VEGFA genetic variations might influence response/resistance of FOLFIRI plus cetuximab treatment in mCRC patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Polymorphism, Genetic; Retrospective Studies; Treatment Outcome; Vascular Endothelial Growth Factor A

BRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC), leading to a median Progression Free Survival (PFS) of 4-6months with first-line conventional treatments. Our group recently reported in a retrospective exploratory analysis of a phase II trial that FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab might allow to achieve remarkable results in terms of PFS and Overall Survival (OS) also in this poor-prognosis subgroup. The aim of this work was to prospectively validate our retrospective finding.. This phase II trial was designed to detect an increase in 6month-Progression Free Rate (6m-PFR) from 45% to 80% in a population of BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab. Secondary end-points were PFS, OS, response rate (RR) and the analysis of outcome parameters in the pooled population consisting of both retrospectively and prospectively included patients. This trial is registered with ClinicalTrials.gov, number NCT01437618.. Two-hundred-fourteen potentially eligible mCRC patients were screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. At a median follow up of 25.7months, 6m-PFR was 73%. Median PFS and OS were 9.2 and 24.1months, respectively. In the pooled population, at a median follow up of 40.4months, 6m-PFR was 84%. Median PFS and OS were 11.8 and 24.1months, respectively. Overall RR and disease control rate were 72% and 88%, respectively.. Lacking randomised trials in this specific molecular subgroup, FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant mCRC patients.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Prospective Studies; Proto-Oncogene Proteins B-raf; Retrospective Studies; Survival Rate; Treatment Outcome

The antiangiogenic agent aflibercept (ziv-aflibercept in the United States) in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) significantly improved survival in a phase III study of patients with metastatic colorectal cancer (mCRC) previously treated with an oxaliplatin-based regimen. In the present analysis, outcomes were evaluated in prespecified subgroups to assess the consistency of the treatment effect.. Patients were randomised to receive FOLFIRI plus aflibercept or placebo every 2weeks until disease progression or unacceptable toxicity occurred. Efficacy and safety outcomes were analysed with respect to demographic and baseline characteristics, and stratification factors (prior bevacizumab treatment and Eastern Cooperative Oncology Group performance status).. Median overall survival (OS, months [95.34% confidence interval (CI)]) for aflibercept versus placebo was 12.5 (10.8-15.5) versus 11.7 (9.8-13.8) in patients with prior bevacizumab treatment and 13.9 (12.7-15.6) versus 12.4 (11.2-13.5) in patients with no prior bevacizumab treatment. The p value for interaction was 0.5668, indicating there was no heterogeneity in these subgroups. For OS and progression-free survival (PFS), there was a significantly greater benefit (at the 2-sided 10% level) of treatment for patients with liver only metastases versus patients with no liver metastases/liver metastases with other organ involvement (p value for interaction: 0.0899 [OS]; 0.0076 [PFS]). There was no evidence of heterogeneity in treatment effect in any of the other subgroups examined.. The benefits of aflibercept in combination with FOLFIRI in patients with mCRC previously treated with oxaliplatin were maintained across the specified patient subgroups, including in patients with or without prior bevacizumab treatment.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Diarrhea; Double-Blind Method; Drug Administration Schedule; Fatigue; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Middle Aged; Neoplasm Metastasis; Neutropenia; Prospective Studies; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Treatment Outcome

As part of a comparative phase II study of eniluracil/5-FU/Lv vs. capecitabine (Xeloda), an oral 5-FU prodrug for MBC, patients with rapid PD during capecitabine therapy crossed over to take eniluracil/5-FU/Lv.. Ten evaluable patients with radiologically documented PD within 70 days of capecitabine treatment were treated with a modified oral weekly eniluracil/5-FU/Lv regimen.. After switching to eniluracil/5-FU/Lv, 3 (30%) patients had PR. Six (60%) had SD, producing a total of 90% with PR or SD. The median PFS was 140 days (vs. 42.5 days for capecitabine). Four (40%) patients had > 7 months PFS. Eniluracil/5-FU/Lv was well tolerated with mild to moderate diarrhea and nausea as the most common side effects.. These positive efficacy and safety results encourage a larger study in patients with rapid PD during capecitabine treatment. Eniluracil/5-FU/Lv might enable these patients to continue with oral 5-FU rather than switching to the generally less well tolerated intravenous microtubule-interfering agents. In addition, the eniluracil/5-FU/Lv regimen might also provide any overall survival contribution of 5-FU that, for pharmacokinetic reasons, was not provided by capecitabine and would not be provided if these patients progressed directly to the other approved treatments.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Treatment Failure; Uracil

The aim of this study was to investigate the impact of midgut versus hindgut as the primary tumor site in patients with metastatic colorectal cancer (mCRC) receiving chemotherapy with FuFIRI or mIROX. We analyzed 423 patients from a phase III trial that randomized patients in a 1 : 1 fashion to either FuFIRI or mIROX. The cohort was grouped into midgut (n=82) and hindgut (n=341) primary tumors. The primary tumor site (midgut vs. hindgut) was correlated with parameters of treatment efficacy and survival. Our cohort comprised 82 patients presenting with primary midgut tumors and 341 with primary hindgut tumors. Tumors of midgut origin compared with hindgut origin were associated with inferior outcome. Objective response rate was 37 versus 43% (P=0.34), median progression-free survival was 6.0 versus 8.2 months (P=0.024, hazard ratio: 0.75), and median overall survival was 13.6 versus 21.8 months (P=0.001, hazard ratio: 0.65). Patients with midgut mCRC showed a clear trend toward inferior outcome in both study arms. However, the effect appeared less pronounced in the mIROX arm. Further datasets from large trials with various regimens are required as confirmation.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Young Adult

The GOLFIG-2 phase III trial was designed to compare the immunobiological activity and antitumor efficacy of GOLFIG chemoimmunotherapy regimen with standard FOLFOX-4 chemotherapy in frontline treatment of metastatic colorectal cancer (mCRC) patients. This trial was conceived on the basis of previous evidence of antitumor and immunomodulating activity of the GOLFIG regimen in mCRC. GOLFIG-2 is a multicentric open/label phase III trial (EUDRACT: 2005-003458-81). Chemo-naive mCRC patients were randomized in a 1:1 ratio to receive biweekly standard FOLFOX-4 or GOLFIG [gemcitabine (1000 mg/m(2), day 1); oxaliplatin (85 mg/m(2), day 2); levofolinate (100 mg/m(2), days 1-2), 5-fluorouracil (5-FU) (400 mg/m(2) in bolus followed by 24 h infusion at 800 mg/m(2),days 1-2), sc. GM-CSF (100 μg, days 3-7); sc. aldesleukin (0·5 MIU bi-daily, days 8-14 and 17-30)] treatments. The study underwent early termination because of poor recruitment in the control arm. After a median follow-up of 43.83 months, GOLFIG regimen showed superiority over FOLFOX in terms of progression-free survival [median 9·23 (95% confidence interval (CI), 6·9-11.5) vs. median 5.70 (95% CI, 3.38-8.02) months; hazard ratio (HR): 0.52 (95% CI, 0.35-0.77), P=0·002] and response rate [66.1% (95% CI, 0.41-0.73) vs. 37·0% (95% CI, 0.28-0.59), P=0.002], with a trend to longer survival [median 21.63 (95% CI, 18.09-25.18) vs. 14.57 mo (95% CI, 9.07-20.07); HR: 0·79 (95% CI, 0.52-1.21); P=0.28]. Patients in the experimental arm showed higher incidence of non-neutropenic fever (18.5%), autoimmunity signs (18.5%), an increase in the number of monocytes, eosinophils, CD4(+) T lymphocytes, natural killer cells, and a decrease in immunoregulatory (CD3(+)CD4(+)CD25(+)FoxP3(+)) T cells. Taken together, these findings provide proof-of-principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-2; Leucovorin; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

We aim to test the hypothesis that high plasma YKL-40 is associated with short progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with first-line oxaliplatin and 5-flourouracil with or without cetuximab.. A total of 566 patients in the NORDIC VII Study were randomized 1∶1∶1 to arm A (Nordic FLOX), arm B (Nordic FLOX + cetuximab), or arm C (Nordic FLOX + cetuximab for 16 weeks followed by cetuximab alone as maintenance therapy). Pretreatment plasma samples were available from 510 patients. Plasma YKL-40 was determined by ELISA and dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects.. Pretreatment plasma YKL-40 was elevated in 204 patients (40%), and median YKL-40 was higher in patients with mCRC than in healthy subjects (age adjusted, P<0.001). Patients with elevated YKL-40 had shorter PFS than patients with normal YKL-40 (7.5 vs. 8.2 months; hazard ratio (HR)  = 1.27 95% confidence interval (CI) 1.05-1.53 P = 0.013) and shorter OS (16.8 vs. 23.9 months; HR = 1.33, 1.04-1.69, P = 0.024). Multivariate Cox analysis demonstrated that elevated pretreatment YKL-40 was an independent biomarker of short OS (HR = 1.12, 1.01-1.25, P = 0.033). The ratio of the updated plasma YKL-40 (i.e. level after 1, 2, 8 weeks of treatment, and at end of treatment compared to the baseline level) was associated with OS (HR = 1.27, 1.06-1.52, P = 0.011).. Plasma YKL-40 is an independent prognostic biomarker in patients with mCRC treated with first-line oxaliplatin-based therapy alone or combined with cetuximab.

Topics: Adipokines; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Case-Control Studies; Cetuximab; Chitinase-3-Like Protein 1; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Fluorouracil; Follow-Up Studies; Humans; Lectins; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate; Young Adult

Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer.. We assessed device placement, use during treatment, associated clinical outcomes and infusion pump performance in the NO16966 trial.. Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU)+oxaliplatin) than XELOX (capecitabine+oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6-4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction.. Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Catheterization, Central Venous; Cohort Studies; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaloacetates; Vascular Access Devices

This study was designed to evaluate (1) the impact of relative dose intensity (RDI) on tumor response and survival outcomes and (2) the influence of dose reduction and schedule modification on outcomes in patients with metastatic colorectal cancer (mCRC).. Pooled datasets from two previous phase II trials of FOLFIRI (CCOG-0502; n = 36) and mFOLFOX6 (CCOG-0704; n = 30) in patients with mCRC were analyzed retrospectively. The RDIs of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). To assess the effects of dose reduction and schedule modification, the effects of dose index (DI) and time index (TI) on outcomes were evaluated.. The median RDIs of irinotecan in FOLFIRI and oxaliplatin in mFOLFOX6 were 80 and 79 %, respectively. Higher RDI of irinotecan in FOLFIRI was associated with significant improvements in RR (65 vs. 6 %, p < 0.01), DCR (100 vs. 59 %, p < 0.01), PFS (9.9 vs. 5.6 months, p < 0.01) and OS (26.7 vs. 12.9 months, p = 0.01) and was the only independent factor associated with PFS [hazard ratio (HR) 8.48, p < 0.01). Higher RDI of oxaliplatin in FOLFOX was significantly associated with DCR (65 vs. 6 %, p < 0.01), and higher TI of oxaliplatin was the only independent factor associated with PFS (HR 2.74, p = 0.04).. RDIs of irinotecan and oxaliplatin affected clinical outcomes. Dose reductions in irinotecan, as indicated by DI, and time delays in oxaliplatin, as indicated by TI, were the only independent prognostic factors predicting PFS in patients receiving FOLFIRI and FOLFOX6, respectively.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Analysis; Treatment Outcome

To evaluate the effectiveness of low-dose radiation therapy (LDRT) and FOLFIRI-bevacizumab (FOLFIRI-B) combination in metastatic colorectal cancer.. The primary objective of the study is to raise the clinical complete response (CR) rate from 5% to 25%. Secondary objectives include toxicity and progression-free survival. Patients underwent 12 FOLFIRI-B cycles plus two daily LDRT (20 cGy/6-hour interval) on the first and second days of each cycle.. CR and toxicity of 10 patients are reported. Considering irradiated sites, 10/10 patients had clinical partial response (PR) (7/10) or CR (3/10). Three clinical PR patients subsequently underwent surgery and reported a pathological CR in the irradiated sites. Grade 3-4 toxicities rate was 30%. With a median follow-up of 29 months (range: 12-49 months), 2/10 progression of disease in irradiated sites and 3/5 in non-irradiated sites were observed.. The very high response rate requires urgent verification in a larger patient series.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemoradiotherapy; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies

With a median overall survival of only 9-13 months in patients with advanced gastric cancer (GC), the quality of life (QoL) during the palliative treatment remains a key issue. Furthermore, when combinations of two or three drugs are used, the impact on QoL should be carefully evaluated. This was studied within the GATAC trial in patients sequentially treated with docetaxel and irinotecan with 5-fluorouracil and leucovorin (5-Fu/Lv). Patients with previously untreated advanced GC were randomly assigned to start with docetaxel 45 mg/m(2) (arm T) or irinotecan 180 mg/m(2) (arm C) with bolus and 44 h infusion of 5-Fu/Lv (D1, q2 weeks). After four courses, there was a prescheduled crossover to the alternative regimen for four additional courses. QoL was measured with the EORTC QLQ-C30 questionnaire at the start of the treatment, at crossover and after completing treatment with both regimens. Eighty-one patients were randomized, and 78 patients started treatment. A total of 191 completed QoL questionnaires were collected. There were no statistically significant differences in QoL scores between the two treatment groups and no changes in mean scores during the 16 weeks of treatment. During the last 8 weeks of treatment, a significantly larger portion of patients with radiological response reported sustained or better QoL scores than those with no radiological response (82 vs. 50%, p = 0.007). Chemotherapy in advanced GC did not affect QoL average scores. Patients with non-responding tumours reported more often a decline in the global QoL score. The concept of the pre-scheduled switch of chemotherapy regimens prior to progression should be further studied in this disease, as it appears effective, tolerable and not to negatively affect QoL.

Topics: Adult; Aged; Antineoplastic Agents; Camptothecin; Docetaxel; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Quality of Life; Stomach Neoplasms; Surveys and Questionnaires; Taxoids; Treatment Outcome

Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) are believed to mediate angiogenesis in colorectal cancer (CRC). Ramucirumab (RAM; IMC-1121B) is a human IgG1 monoclonal antibody that inhibits VEGF ligand binding to VEGFR-2, inhibiting VEGFR-2 activation and signaling.. Patients with metastatic CRC, Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function who had not received chemotherapy for metastatic disease received RAM and the modified FOLFOX-6 regimen every 2 weeks. Endpoints included progression-free survival (PFS), objective response rate, overall survival, and safety. The sample size was based on a potentially improved median PFS from 8 months to 11 months.. Forty-eight patients received therapy. Median PFS was 11.5 months (95% confidence interval [CI]: 8.6-13.1 months). The objective response rate was 58.3% (95% CI: 43.21-72.39). The disease control rate (complete or partial response plus stable disease) was 93.8% (95% CI: 82.8-98.7). Median overall survival was 20.4 months (95% CI: 18.5-25.1 months). The most frequent grade 3-4 adverse events included neutropenia (grade 3: 33.3%; grade 4: 8.3%), hypertension (grade 3: 16.7%), and neuropathy (grade 3: 12.5%). Two patients died during the study due to myocardial infarction and cardiopulmonary arrest.. RAM may enhance the efficacy of modified FOLFOX-6 chemotherapy with an acceptable safety profile in metastatic CRC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Protein Binding; Ramucirumab; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Standard treatment for patients with unresectable colorectal cancer metastases includes chemotherapy regimens based on irinotecan, oxaliplatin, fluoropyrimidines, anti-vascular endothelial growth factor therapy, and anti-EGFR. Additional therapeutic options are needed for patients with good performance status who have disease progression during or after standard therapies.. A nonrandomized phase II study was modeled as a two-stage Chen design. Eligible patients had a diagnosis of metastatic colorectal cancer (mCRC) with progression after prior cytotoxic regimens based on oxaliplatin and irinotecan. Treatment consisted of mitomycin C in combination with high-dose 5-fluorouracil (5-FU) and folinic acid (the MLF regimen; mitomycin C as an intravenous bolus of 6 mg/m² i.v. on days 1 and 22 every 7 weeks; folinic acid at 250 mg/m² in combination with 5-FU at 2,600 mg/m² as a continuous intravenous infusion (24 hours) weekly for 6 of every 7 weeks.. The median age of the 74 eligible patients was 62 years (range: 47-79 years). In these heavily pretreated patients with mCRC, the MLF regimen was the fourth or fifth line in more than 60% of the patients. Two patients (3.2%) achieved a partial response, and 33 (53.2%) achieved a best response of stable disease, defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Median progression-free survival was 4.9 months. The median overall survival was 9.7 months. The most common nonhematologic side effects included mucositis (24.4% for all grades, and 9.5% with grade 3/4), diarrhea (15.0% for all grades, 13.6% with grade 3/4), fatigue (44.7% for all grades, 13.6% with grade 3/4), nausea (12.3% for all grades, 6.8% with grade 3/4), and peripheral neuropathy (17.6% for all grades, 2.7% with grade 3/4). Among the most frequent hematological toxicities were neutropenia (27.1% for all grades, 14.9% with grade 3/4), thrombocytopenia (18.9% for all grades, 8.1% with grade 3/4), and anemia (13.6% for all grades, 4.1% with grade 3/4). Dose reductions due to adverse events were necessary in 29 of 74 patients (37.6%), and discontinuation of therapy due to toxicity was necessary for 14 of 74 patients (18.2%).. Our study shows the MLF regimen can be administered safely to patients with heavily pretreated mCRC. Median progression-free and overall survival compares favorably with other options used or approved in this setting. A randomized trial in this setting should be considered.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitomycin; Neoplasm Metastasis; Prospective Studies; Treatment Outcome

This study was the first multicenter phase II study of cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type mCRC as a second-line treatment in Japan including BRAF and PIK3CA genotyping.. Tumors of 112 pre-registered patients were genotyped for KRAS, BRAF, and PIK3CA. The primary study end-point was response rate, and secondary end-points were progression-free survival (PFS), overall survival (OS), and safety.. Sixty-seven patients (59.8%) were EGFR-positive and KRAS wild-type. The mean age of the enrolled patients (n=60) was 62.6 years (range=37-82 years). The response rate was 31.7% and stable disease was observed in 53.3%. No objective response was observed in patients with BRAF or PIK3CA mutations. The median PFS and OS were 7.4 and 18.2 months, respectively. Grade-3/4 adverse events were leucopenia (26.7%), neutropenia (43.3%), paronychia (10.0%), fissure (10.0%) and acne-like rash (5.0%).. Second-line cetuximab plus FOLFIRI was effective and well-tolerated.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Genes, ras; Genotype; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Tumor Burden

Irinotecan, leucovorin, and bolus and continuous-infusion 5-fluorouracil administered every two weeks (FOLFIRI regimen) is active in patients with metastatic colorectal cancer. However, the efficacy and toxicity of this regimen in Japanese patients with metastatic colorectal cancer remain unknown.. We investigated the maximum tolerated dose, dose-limiting toxicity, and recommended dose at Step 1. Twenty-one patients with metastatic colorectal cancer were enrolled in Step 1. At the five dose levels, fixed doses of bolus 5-fluorouracil (400 mg/m(2)) and leucovorin (200 mg/m(2)) were administered in combination with escalating doses of irinotecan from 120-180 mg/m(2) with 46-h continuous infusion of 5-fluorouracil 2000-3000 mg/m(2) every two weeks. In Step 2, an additional 24 patients received the recommended doses determined in Step 1, and safety and antitumor efficacy were evaluated in terms of tumor response.. No dose-limiting toxicities were observed at dose levels 1-4. Four out of eight patients experienced a dose-limiting toxicity at level 5; therefore, this level was considered the maximum tolerated dose. Consequently, the recommended doses were determined to be 180 mg/m(2) of irinotecan and 2,400 mg/m(2) of 5-fluorouracil in continuous i.v. infusion. At this level (FOLFIRI-180), National Cancer Institute common terminology criteria grade 3-4 neutropenia, leukopenia, and vomiting were common but manageable. Other hematological and non-hematological toxicities were mild. Seven out of 23 response-assessable patients achieved an objective response (response rate=30%).. This FOLFIRI-180 regimen is manageable and effective in Japanese patients with metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Japan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Treatment Outcome

The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab-FOLFOX4 significantly improved progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study.. Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled.. A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months [95% confidence interval (CI) 9.3-11.4 months] for arm 1 and 8.6 months (95% CI 7.5-9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67-0.95; P = 0.01. Median overall survival (OS) for WT KRAS mCRC was 23.9 months (95% CI 20.3-27.7 months) for arm 1 and 19.7 months (95% CI 17.6-22.7 months) for arm 2; HR = 0.88; 95% CI 0.73-1.06; P = 0.17 (68% OS events). An exploratory analysis of updated survival (>80% OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95% CI 0.70-0.98; P = 0.03 for WT KRAS mCRC. The adverse event profile was consistent with the primary analysis.. In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab-FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Quality of Life

This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.. Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.. Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.. While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Monitoring; Early Termination of Clinical Trials; Everolimus; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Metastasis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Protein Kinase Inhibitors; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases

A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects.. We randomly assigned 508 patients with untreated metastatic colorectal cancer to receive either FOLFIRI plus bevacizumab (control group) or FOLFOXIRI plus bevacizumab (experimental group). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival.. The median progression-free survival was 12.1 months in the experimental group, as compared with 9.7 months in the control group (hazard ratio for progression, 0.75; 95% confidence interval [CI], 0.62 to 0.90; P=0.003). The objective response rate was 65% in the experimental group and 53% in the control group (P=0.006). Overall survival was longer, but not significantly so, in the experimental group (31.0 vs. 25.8 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 1.00; P=0.054). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the experimental group.. FOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in patients with metastatic colorectal cancer and increased the incidence of some adverse events. (Funded by the Gruppo Oncologico Nord Ovest and others; ClinicalTrials.gov number, NCT00719797.).

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

This phase II study aims to evaluate the efficacy and safety of biweekly cetuximab in combination with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) as first-line treatment of metastatic wild-type KRAS colorectal cancer.. Previously untreated patients with wild-type KRAS tumours received biweekly cetuximab (500 mg/m2 on day 1) plus FOLFOX-4 (oxaliplatin 85 mg/m2 on day 1, leucovorin 200 mg/m2 on days 1 and 2, and fluorouracil as a 400 mg/m2 bolus followed by a 22-hour 600 mg/m2 infusion on day 1 and 2). Treatment was continued until disease progression, onset of unacceptable toxicities, metastases surgery, or discontinuation request. The primary endpoint was ORR.. The intention-to-treat population included 99 patients with a median age of 64.1 years (range, 34-82). The ORR was 60.6% (95% CI, 50.3% to 70.3%). The median follow-up was 17.8 months; the median OS and PFS were 20.8 and 10.1 months, respectively. Metastases from colorectal cancer were surgically resected in 26 (26.3%) patients, with complete resection achieved in 18 (69.2%) patients. Median PFS and OS in patients undergoing metastatic resection were 12.6 and 29.5 months, respectively. The most common grade 3-4 toxicities were neutropenia (32.3%), acne-like rash (15.2%) and diarrhoea (11.1%).. The efficacy of the biweekly combination of cetuximab with FOLFOX-4 in patients with wild-type KRAS tumours supports the administration of cetuximab in a dosing regimen more convenient for patients and healthcare providers. The activity of the biweekly administration is similar to what has been reported for the weekly regimen. Reported toxicity was also consistent with the known toxicity profile of weekly cetuximab.. EudraCT Number 200800690916.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Treatment Outcome; Tumor Burden

The aim of this study was to evaluate the impact of pathologic complete response (pCR) on outcome in patients with gastric or esophagogastric junction (EGJ) adenocarcinoma after neoadjuvant docetaxel/platin/fluoropyrimidine-based chemotherapy.. Patients received at least one cycle of chemotherapy for potentially operable disease. Pretreatment clinicopathologic factors and pCR were investigated. Disease-free survival (DFS), overall survival (OS) and tumor-related death were correlated with pCR.. One hundred twenty patients were included in this analysis. Eighteen patients (15%) achieved a pCR. Tumor localization in the EGJ was identified as the only significant predictor of pCR (P = 0.019). Median follow-up was 41.1 months. Median DFS and OS for all patients were 24.1 and 48.6 months, respectively. Median DFS for patients with a pCR was not reached versus 22.1 months non-pCR patients (hazard ratio, HR 0.38; 3-year DFS: 71.8% and 37.7%, respectively, P = 0.018). While OS was not significantly different, the risk for tumor-related death was significantly lower for pCR patients compared with non-pCR patients (3-year cumulative incidences of 6.4% and 45.4%, respectively, P = 0.009).. A pCR following preoperative docetaxel/platin/fluoropyrimidine indicates favorable outcome in patients with gastric or EGJ adenocarcinoma. Tumor location in the EGJ is associated with a higher pCR rate.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Deoxycytidine; Disease-Free Survival; Docetaxel; Esophageal Neoplasms; Esophagogastric Junction; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Remission Induction; Stomach Neoplasms; Survival; Survival Rate; Taxoids; Vitamin B Complex

The method of combined neoadjuvant treatment of resectable cancer recti, consisting of preoperative radiaton therapy, using big-fractionized intensive irradiation on the endolymphatic chemotherapy background together with fluorouracil with following surgical intervention (main group), in terms up to 72 h, was elaborated in the clinic. The patients, to whom the chemotherapy and radiation therapy were conducted, were included into control groups. Postoperative complications have had occurred in 8 (12.5%) patients of the main group and in 10 (15.87%) and 13 (14.29%)--in control groups. The five-year survival indices in the main group have constituted (73.5 +/- 6.3)%, and in control groups--(64.6 +/- 5.8) and (64.4 +/- 6.8)%. The local recurrence rate in the main group have constituted (6.2 +/- 3.0)%, and of the remote metastatizing--(15.6 +/- 4.5)%.

Topics: Antimetabolites, Antineoplastic; Chemoradiotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local

The FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12-13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies.. We conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², and folinate 200 mg/m² on day 1, followed by fluorouracil 3000 mg/m² as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12-13-61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m² after two of the first three patients reported grade 3-4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR).. Eighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7-12.9 months). After amendment, most common grade 3-4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered.. Adding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras-BRAF wild-type patients are promising.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; ErbB Receptors; Female; Fluorouracil; GTP Phosphohydrolases; Humans; Leucovorin; Male; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome

To investigate the safety and efficacy of pemetrexed combined with chemotherapy as second or third line in patients with stage IV colorectal cancer (CRC).. This trial was conducted to evaluate the effectiveness and safety of pemetrexed given to patients with recurrent or metastatic colorectal carcinoma who previously received 5-FU-based chemotherapy. All patients were required to have a histological diagnosis of colorectal adenocarcinoma with measurable metastatic disease and prior chemotherapy. Patients received pemetrexed at a dose of 500 mg/m2 by 10 minute infusion on day 1, repeated every 21 days. Doses were modified depending on nadir counts. Combined chemotherapy included Oxaliplatin, Irinotecan and cis-platinum.. Thirty patients were enrolled and twenty-nine were evaluable for response. One patient did not have repeat radiological testing to determine response because he went off study after only one cycle of treatment for economic reasons. For 29 evaluable patients, 1 partial response, 6 stable disease and 22 progressive disease were recorded. Response rate was 3.45% (1/29). All responses occurred in patients receiving a starting dose of pemetrexed 500 mg/m2. Median time to progression for all eligible patients was 2.5 months. The most common toxicities experienced were mild to moderate fever, hepatic damage, myelosuppression, nausea, vomiting, constipation, abdominal pain, diarrhea, and skin rash.. Pemetrexed at 500 mg/m2 given every three weeks combined with chemotherapy is associated with moderate response and good tolerability in patients with stage IV CRC.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Glutamates; Guanine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pemetrexed; Prognosis

To evaluate the MIROX strategy (6 FOLFOX7 cycles followed by 6 FOLFIRI cycles) in patients with resected or resectable metastases from colorectal cancer.. This trial compared the MIROX strategy to 12 cycles of simplified LV5FU2 (sLV5FU2). Chemotherapy was perioperative or adjuvant, at the investigator's decision, with stratification for this parameter. The primary objective was disease-free survival (DFS). The trial was interrupted in 2004, following the results of the adjuvant MOSAIC trial showing superiority of FOLFOX4 over LV5FU2.. Thirty-nine patients were included: 20 in MIROX arm and 19 in sLV5FU2 arm. Median DFS was higher in the MIROX arm (not reached versus 24.8 months, P = 0.044). MIROX regimen was well tolerated; 5/20 patients experienced a Grade 3 sensoryneuropathy.. The MIROX strategy demonstrated promising efficacy, but this must be considered cautiously due to the small number of patients included. The pragmatic approach adopted for the treatment chronology is feasible.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

The aim of this study was to evaluate 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET for early prediction of the standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX).. The main eligibility criteria included histologically confirmed mCRC, ≥ 1 extrahepatic measurable lesions, and no prior chemotherapy in a metastatic setting. Chemotherapy consisted of leucovorin on day 1, followed by the continuous infusion of 5-FU on days 1 and 2, and oxaliplatin on day 3. In the second and subsequent cycles of chemotherapy, oxaliplatin was administered simultaneously with leucovorin on day 1. (18)F-FLT PET scans were obtained 3 times during the first cycle of chemotherapy: before chemotherapy, 24 h after infusion of 5-FU (day 2), and 48 h after completion of chemotherapy (day 5). The maximum standardized uptake value (SUVMAX) of (18)F-FLT was measured. Treatment responses were assessed by CT after 3 cycles of FOLFOX.. Eighteen patients were included in the study. The response rate after 3 cycles of FOLFOX was 27.8% (5/18). The SUVMAX was increased in responders (P = 0.043) and nonresponders (P < 0.001) on day 2 and was decreased, compared with baseline values, on day 5 in responders only (P = 0.043). Receiver-operating-characteristic curve analysis indicated that the use of a threshold of an SUVMAX increase on day 2 of ≤ 45.8% resulted in a sensitivity of 100%, specificity of 69.2%, and relative risk of 2.250 (P = 0.029) for the diagnosis of responders. Use of a threshold of an SUVMAX decrease on day 5 of ≥ 10.6% resulted in a sensitivity of 100%, specificity of 76.9%, and relative risk of 2.667 (P = 0.007). Patients with low (18)F-FLT flare tended to have longer survivals than patients with high flare (2-y overall survival rate, 77.8% vs. 44.4%; P = 0.051).. The (18)F-FLT flare observed during 5-FU infusion was associated with poor treatment response in patients with mCRC. The degree of (18)F-FLT flare might be used to predict the outcome of patients who receive infusional 5-FU-based chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dideoxynucleosides; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Positron-Emission Tomography; Survival Analysis; Time Factors; Treatment Outcome

Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.. In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.. Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.. Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; ErbB Receptors; Fluorouracil; Genes, ras; GTP Phosphohydrolases; Humans; Leucovorin; Membrane Proteins; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins

The study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer.. A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed.. In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7).. Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; TNF-Related Apoptosis-Inducing Ligand

In patients with previously untreated metastatic colorectal cancer (mCRC), we conducted a phase 1b/randomized phase 2 trial to define the safety, tolerability, and efficacy of mFOLFOX6 plus bevacizumab (mFOLFOX6/bev) with conatumumab, an investigational, fully human monoclonal IgG1 antibody that specifically activates death receptor 5 (DR5).. Twelve patients were enrolled in a phase 1b open-label dose-escalation trial of conatumumab with mFOLFOX6/bev; thereafter, 190 patients were randomized 1:1:1 to receive mFOLFOX6/bev in combination with 2 mg/kg conatumumab, 10 mg/kg conatumumab, or placebo. Therapy cycles were repeated every 2 weeks until disease progression or the occurrence of unacceptable toxicity.. In phase 1b, conatumumab with mFOLFOX6/bev was tolerated without apparent added toxicity over mFOLFOX6/bev alone. In phase 2, conatumumab with mFOLFOX6/bev did not confer a benefit in progression-free survival when compared with placebo with mFOLFOX6/bev. Toxicity was similar in all treatment arms. Following treatment, similar increases in circulating caspase-3 levels were observed in all arms.. Conatumumab with mFOLFOX6/bev did not offer improved efficacy over the same chemotherapy with placebo in first-line treatment of patients with mCRC. These data do not support further development of conatumumab in advanced CRC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Caspase 3; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Receptors, TNF-Related Apoptosis-Inducing Ligand

Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, shows activity in multiple tumor types, including those refractory to previous antiangiogenic therapy. This randomized, multicenter, parallel-group, open-label phase II trial compared axitinib with bevacizumab each in combination with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) for second-line treatment of metastatic colorectal cancer.. Patients were randomized 1:1 to axitinib 5 mg twice daily or bevacizumab 5 mg/kg every 2 weeks plus modified FOLFOX-6 (if previously treated with irinotecan) or FOLFIRI (if previously treated with oxaliplatin) and were stratified by performance status and prior bevacizumab therapy. Primary endpoint was progression-free survival.. In 171 patients, progression-free survival was 7.6 months with axitinib/FOLFOX vs. 6.4 months with bevacizumab/FOLFOX (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.55-1.96; 1-sided P = .55) and 5.7 months with axitinib/FOLFIRI vs. 6.9 months with bevacizumab/FOLFIRI (HR, 1.27; 95% CI, 0.77-2.11; 1-sided P = .83). Overall survival was 17.1 vs. 14.1 months with axitinib/FOLFOX and bevacizumab/FOLFOX (HR, 0.69; 95% CI, 0.37-1.27; 1-sided P = .12) and 12.9 vs. 15.7 months with axitinib/FOLFIRI and bevacizumab/FOLFIRI (HR, 1.36; 95% CI, 0.82-2.24; 1-sided P = .88). More grade ≥ 3 adverse events (eg, diarrhea, fatigue, decreased appetite) and treatment discontinuations due to adverse events occurred with axitinib.. Compared with bevacizumab, axitinib did not improve outcomes when added to second-line chemotherapy for metastatic colorectal cancer. With current dosing regimens, axitinib plus FOLFOX or FOLFIRI seems to be less well tolerated than bevacizumab-based regimens.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Imidazoles; Indazoles; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Young Adult

Four-drug regimens, such as FIr-B/FOx schedule, can improve efficacy of first-line treatment of metastatic colorectal cancer (MCRC) patients. The present study specifically evaluates feasibility of FIr-B/FOx first-line intensive regimen in fit young-elderly MCRC patients, representing approximately 40% of overall MCRC patients. Activity, efficacy, and safety were equivalent to overall MCRC patients, not significantly different according to KRAS genotype. Clinical outcome was significantly prolonged in liver-limited compared to other/multiple metastatic disease. Safety evaluation of the individual young-elderly patient showed that limiting toxicity syndromes (LTS) in multiple sites were significantly increased, compared to LTS in single site, with respect to non-elderly patients.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carboplatin; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Demography; DNA Mutational Analysis; Dose-Response Relationship, Drug; Female; Fluorouracil; Genotype; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome

Elderly patients are generally underrepresented in the study populations of combination chemotherapy trials. This study evaluates the efficacy and safety of a modified FOLFOX regimen in elderly patients with metastatic gastric cancer and presenting associated disease(s).. A total of 43 patients aged ≥70 years received oxaliplatin 85 mg/m(2) together with 6S-leucovorin 200 mg/m(2) on day 1, followed by a 46-h infusion of 5-fluorouracil 2,400 mg/m(2), every 2 weeks. Assessment of response was performed every four cycles according to RECIST criteria.. Median patient age was 74 years (range, 70-83 years). Overall response rate was 34.9% [95% confidence interval (CI), 20.6-49.1, with 3 complete responses and 12 partial responses. Grade 3 neutropenia occurred in 4 patients (9.3%), fatigue in 3 patients (7.0%), and vomiting in 2 patients (4.6%). Grade 2 and 3 peripheral neuropathy was observed in 5 patients (11.6%) and 1 patient (2.3%), respectively. No treatment-related death was observed. Median progression-free and overall survival were 6.8 and 10.5 months, respectively.. This modified FOLFOX regimen is an active and well-tolerated treatment for elderly patients with metastatic gastric cancer and also represents a good therapeutic option in patients with associated disease(s).

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Stomach Neoplasms; Survival Rate; Treatment Outcome

Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).. Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.. A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.. Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyridines; ras Proteins; Treatment Outcome

In the CRYSTAL study adding cetuximab to first-line FOLFIRI significantly improved outcome in patients with KRAS wild-type metastatic colorectal cancer. Quality of life (QoL) was assessed, and associations with tumour response and survival were investigated.. The European Organization for Research and Treatment of Cancer QoL questionnaire-core 30 was used, focusing on global health status (GHS)/QoL and social functioning scales. Radiological response was assessed by an independent review committee.. QoL was evaluable in 627/666 patients (94%) with KRAS wild-type tumours; of these 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. Pattern mixture analysis revealed no significant differences for GHS/QoL (P=0.12) and social functioning scores (P=0.43) between the treatment arms. In additional analyses: early skin reactions in patients receiving cetuximab did not significantly affect these QoL scales, and tumour response was more common (58% versus 40%, P=0.0002) and survival longer (Hazard ratio 1.68, P<0.0001) in asymptomatic compared with symptomatic patients at baseline. Adding cetuximab to FOLFIRI was associated with significantly higher tumour response irrespective of patient baseline symptomatic status, and enhanced symptom relief from baseline in those whose tumours had responded.. Adding cetuximab to FOLFIRI improved response rate and survival without either improving or negatively impacting on GHS/QoL and social functioning.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Quality of Life; ras Proteins; Surveys and Questionnaires; Survival Analysis; Young Adult

This prospective observational study assessed the efficacy of bevacizumab in combination with chemotherapy as preoperative treatment to downsize tumours for radical resection in patients with unresectable metastatic colorectal cancer (mCRC).. Patients with mCRC initially unresectable according to predefined criteria were included. Preoperative treatment consisted of bevacizumab (5 mg/kg) combined with oxaliplatin- or irinotecan-based chemotherapy, which was followed by surgery in patients showing clinical benefit. Resection rate was the primary endpoint. Response rate (RR) and clinical benefit of preoperative chemotherapy, and overall survival (OS) were secondary endpoints.. A total of 120 eligible patients were included and received preoperative treatment. Chemotherapy was irinotecan-based in 73 (61 %) patients, oxaliplatin-based in 25 (21 %) and 22 (18 %) patients received more than one line. A RR of 30 % and a clinical benefit rate of 73 % were observed with preoperative chemotherapy. Metastatic resection was possible in 61 (51 %) patients. Median OS was 33 months (95 % CI 31-NA months) for patients undergoing surgery, and 15 months (95 % CI 11-25 months) in non-operated patients. Thirty-five patients experienced 59 postoperative complications (morbidity rate 57 %).. Preoperative bevacizumab-based chemotherapy offers a high surgical rescue rate in patients with initially unresectable mCRC.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Postoperative Complications; Preoperative Care; Prognosis; Prospective Studies; Survival Rate

Aflibercept, a recombinant fusion protein, is a potent inhibitor of vascular endothelial growth factor (VEGF)-A, VEGF-B, and the placental growth factor (PlGF). The present study was an open-label, sequential-cohort, dose-escalation trial of intravenous aflibercept administered every 2 weeks in combination with 5-fluorouracil, levofolinate, and irinotecan (FOLFIRI) in patients with previously treated metastatic colorectal cancer (mCRC). We aimed to assess the safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary efficacy of the combination therapy to determine the recommended phase II dose (RPTD) for Japanese patients. Two doses of aflibercept (2.0 and 4.0 mg/kg) were set, and DLTs were evaluated in the first 2 cycles. The subjects comprised 16 patients (n = 3 and 13 for 2.0 and 4.0 mg/kg aflibercept, respectively) who received a total of 149 cycles of aflibercept with FOLFIRI. No DLTs were observed at both doses. The frequent adverse events encountered were leukopenia, neutropenia, anemia, diarrhea, fatigue, decreased appetite, stomatitis, dysphonia, nausea, and epistaxis. The most common grade 3/4 adverse events were neutropenia for both doses and hypertension for the 4.0 mg/kg dose. Free aflibercept exposure increased with the dose, whereas exposure to VEGF-bound aflibercept remained similar at both doses. The response rate and progression-free survival at 4.0 mg/kg was 8.3 % and 7.59 months, respectively. In conclusion, the combination of aflibercept and FOLFIRI was well tolerated at both doses. The RPTD of aflibercept in combination with FOLFIRI for Japanese patients with mCRC was determined to be 4.0 mg/kg every 2 weeks. ClinicalTrials.gov identifier: NCT00921661.

Topics: Administration, Intravenous; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asian People; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Vascular Endothelial Growth Factor A

The aims of this study were to establish the maximum tolerated dose (MTD) of oxaliplatin in combination with fixed doses of gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in solid tumors, including advanced pancreatic cancer, and to evaluate the toxicity of the regimen.. Patients with metastatic solid tumors were treated with a regimen consisting of gemcitabine (500 mg/m(2) by fixed-dose-rate infusion), irinotecan (120 mg/m(2)), leucovorin 300 mg, bolus/infusion 5-fluorouracil (400 and 1,500 mg/m2, respectively), and oxaliplatin at doses from 50 to 85 mg/m(2) according to the escalation schema. Treatment was repeated every 14 days.. The study enrolled 25 patients with a median age of 64 years and median Karnofsky performance score of 80. Patients had metastatic adenocarcinomas of pancreas (n = 9), as well as gastroesointestinal, hepatobiliary, or unknown primary tumors. With only one dose limiting toxicity (neutropenia and constipation), the MTD of oxaliplatin was not reached up to the pre-specified maximum level of 85 mg/m(2). Other toxicities predictably included cytopenias, fatigue, sensory neuropathy, nausea/vomiting, diarrhea, and constipation. Four partial responses and ten disease stabilizations were observed. The overall median time to disease progression was 17 weeks (2-110 weeks) with median overall survival of 31.5 weeks (7-139 weeks).. G-FLIE is a tolerable multi-agent chemotherapy regimen with the oxaliplatin dose up to 85 mg/m(2). The combination of full-dose oxaliplatin with gemcitabine, irinotecan, and 5-fluorouracil is feasible with attenuated doses of the drugs, but further optimization is necessary before assessment of efficacy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

To compare the quality of life (QoL) of patients receiving oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine as first-line chemotherapy and to assess whether pretreatment QoL predicts survival in patients with metastatic pancreatic cancer.. Three hundred forty-two patients with performance status 0 or 1 were randomly assigned to receive FOLFIRINOX (oxaliplatin, 85 mg/m(2); irinotecan, 180 mg/m(2); leucovorin, 400 mg/m(2); and fluorouracil, 400 mg/m(2) bolus followed by 2,400 mg/m(2) 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m(2) weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. QoL was assessed using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every 2 weeks.. Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and improvement in emotional functioning (P < .001) was observed in both arms, along with a decrease in pain, insomnia, anorexia, and constipation in both arms. A significant increase in diarrhea was observed in the FOLFIRINOX arm during the first 2 months of chemotherapy. Time until definitive deterioration ≥ 20 points was significantly longer for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation). Physical functioning, constipation, and dyspnea were independent significant prognostic factors for survival with treatment arm, age older than 65 years, and low serum albumin.. FOLFIRINOX significantly reduces QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer. Furthermore, baseline QoL scores improved estimation of survival probability when added to baseline clinical and demographic variables.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Leucovorin; Longitudinal Studies; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Quality of Life; Surveys and Questionnaires; Survival Rate

The objective of this economic evaluation, which was based on patients from two randomized controlled clinical trials (NO16966 and NO16967), was to compare direct medical costs to the Australian health-care system of capecitabine plus oxaliplatin (XELOX) and bolus and/or infusional 5-fluorouracil (5-FU) plus folinic acid combined with oxaliplatin (modified [m] FOLFOX-6) in first-line and second-line treatment of advanced or metastatic colorectal cancer (mCRC).. Direct medical costs were estimated for five treatment settings from a public and private hospital. The costs included in evaluation were for drug acquisition, preparation (oxaliplatin, bolus and infusional 5-FU), administration and wastage. The cost of drug acquisition was calculated based on dosage data and the mean number of treatment cycles from the pivotal studies NO16966 and NO16967. There were no costs associated with preparing capecitabine and leucovorin. An oncology grouping and costing study was performed to determine the relevant administration costs associated with central venous access devices, their placement, maintenance and removal (for oxaliplatin administration) and the continuous infusion of 5-FU via a continuous ambulatory delivery device pump or infuser.. This economic evaluation has shown that treating mCRC patients with XELOX in the first and second-line settings results in average cost savings of $9110 and $7113, respectively, compared with mFOLFOX-6. A multi-way sensitivity analysis demonstrated that the use of XELOX remained cost-saving from an Australian government health budget perspective.. The use of XELOX, compared with mFOLFOX-6, for the treatment of mCRC is cost-saving in the Australian government health budget.

Topics: Antineoplastic Combined Chemotherapy Protocols; Australia; Capecitabine; Colorectal Neoplasms; Cost-Benefit Analysis; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaloacetates; Randomized Controlled Trials as Topic

Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signalling with activity against all three VEGF receptors. Bevacizumab is an anti-VEGF-A monoclonal antibody with clinical benefit in previously treated metastatic colorectal cancer (mCRC).. Patients with mCRC who had progressed following first-line therapy were randomised 1:1:1 to modified (m)FOLFOX6 plus cediranib (20 or 30 mg day(-1)) or bevacizumab (10 mg kg(-1) every 2 weeks). The primary objective was to compare progression-free survival (PFS) between treatment arms.. A total of 210 patients were included in the intent-to-treat (ITT) analysis (cediranib 20 mg, n=71; cediranib 30 mg, n=73; bevacizumab, n=66). Median PFS in the cediranib 20 mg, cediranib 30 mg and bevacizumab groups was 5.8, 7.2 and 7.8 months, respectively. There were no statistically significant differences between treatment arms for PFS (cediranib 20 mg vs bevacizumab: HR=1.28 (95% CI, 0.85-1.95; P=0.29); cediranib 30 mg vs bevacizumab: HR=1.17 (95% CI, 0.77-1.76; P=0.79)) or overall survival (OS). Grade ≥ 3 adverse events were more common with cediranib 30 mg (91.8%) vs cediranib 20 mg (81.4%) or bevacizumab (84.8%).. There were no statistically significant differences between treatment arms for PFS or OS. When combined with mFOLFOX6, the 20 mg day(-1) dose of cediranib was better tolerated than the 30 mg day(-1) dose.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Double-Blind Method; Female; Fluorouracil; Humans; International Agencies; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Quinazolines; Salvage Therapy; Survival Rate; Young Adult

The combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC.. Patients received bevacizumab 7.5mg/kg on day 1 plus XELIRI (irinotecan 200mg/m(2) on day 1 and oral capecitabine 1,000 mg/m(2) bid on days 1-14) every 3 weeks or bevacizumab 5mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400mg/m(2) on day 1 plus 2,400 mg/m(2) as a 46-h infusion, leucovorin 400mg/m(2) on day 1, and irinotecan 180 mg/m(2) on day 1) every 2 weeks. Patients aged ≥ 65 years received a lower dose of capecitabine (800 mg/m(2) twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate.. A total of 145 patients were enrolled (bevacizumab-XELIRI, n=72; bevacizumab-FOLFIRI, n=73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71-90%) in the bevacizumab-XELIRI arm and 85% (95% CI 75-92%) in the bevacizumab-FOLFIRI arm. In both the bevacizumab-XELIRI and bevacizumab-FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab-XELIRI 18%; bevacizumab-FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively).. This randomised non-comparative study demonstrates that bevacizumab-XELIRI and bevacizumab-FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Fatigue; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Neutropenia; Quality of Life; Time Factors; Treatment Outcome; Venous Thrombosis

This double-blind, phase III study aimed to demonstrate that sunitinib plus FOLFIRI (fluorouracil, leucovorin, and irinotecan) was superior to placebo plus FOLFIRI in previously untreated metastatic colorectal cancer (mCRC).. Patients were randomly assigned to receive FOLFIRI and either sunitinib (37.5 mg per day) or placebo (4 weeks on treatment, followed by 2 weeks off [schedule 4/2]) until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, safety, and patient-reported outcomes. The correlation between genotype and clinical outcomes was also analyzed.. In all, 768 patients were randomly assigned to sunitinib plus FOLFIRI (n = 386) or placebo plus FOLFIRI (n = 382). Following a second prespecified interim analysis, the study was stopped because of potential futility of sunitinib plus FOLFIRI. Final results are reported. The PFS hazard ratio was 1.095 (95% CI, 0.892 to 1.344; one-sided stratified log-rank P = .807), indicating a lack of superiority for sunitinib plus FOLFIRI. Median PFS for the sunitinib arm was 7.8 months (95% CI, 7.1 to 8.4 months) versus 8.4 months (95% CI, 7.6 to 9.2 months) for the placebo arm. Sunitinib plus FOLFIRI was associated with more grade ≥ 3 adverse events and laboratory abnormalities than placebo (especially diarrhea, stomatitis/oral syndromes, fatigue, hand-foot syndrome, neutropenia, thrombocytopenia, anemia, and febrile neutropenia). More deaths as a result of toxicity (12 v four) and significantly more dose delays, dose reductions, and treatment discontinuations occurred in the sunitinib arm.. Sunitinib 37.5 mg per day (schedule 4/2) plus FOLFIRI is not superior to FOLFIRI alone and has a poorer safety profile. This combination regimen is not recommended for previously untreated mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Double-Blind Method; Drug Administration Schedule; Fatigue; Female; Fluorouracil; Humans; Indoles; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Pyrroles; Sunitinib; Thrombocytopenia; Treatment Outcome

Squamous cell carcinoma is the main histological subtype of esophageal cancer in the east Asia. Oxaliplatin and fluorouracil are active agents for esophageal carcinoma. The aim of this phase II study was to evaluate the efficacy and safety of oxaliplatin, fluorouracil and leucovorin in patients with metastatic esophageal squamous cell carcinoma (ESCC).. Patients with metastatic ESCC and Eastern Cooperative Oncology Group performance score of 0-2 who had not received prior systemic chemotherapy for metastatic disease were enrolled. Oxaliplatin, 100 mg/m(2), was administered as a 2-h intravenous (i.v.) infusion on day 1. Leucovorin, 400 mg/m(2) i.v., was administered as a 2-h infusion followed by fluorouracil (400 mg/m(2)) i.v. bolus immediately followed by fluorouracil (2,400 mg/m(2)) as a 46-h continuous infusion on days 1 and 2. Chemotherapy was repeated every 14 days.. Between October 2008 and September 2011, fifty-six patients, with a median age of 59 years, were enrolled in this study. The overall response rate was 23.2 % with a disease control rate of 67.9 %. The median progression-free survival (PFS) was 4.4 months, and the median overall survival (OS) was 7.7 months. Median PFS was significantly longer in patients without liver metastasis than those with liver metastasis (5.4 vs 2.4 months, P = 0.003). Partial response was associated with longer PFS (7.2 vs 2.7 months, P = 0.023) and OS (11.3 vs 7.1 months, P = 0.028). Significant difference in OS was noted between those age >65 and ≤ 65 years of age (7.9 vs 3.3 months, P = 0.033). Grade 3/4 neutropenia, leucopenia, anemia and thrombocytopenia occurred in 35.7, 28.6, 10.7 and 10.7 % of patients, respectively. The most common non-hematologic toxicities were fatigue, mucositis, nausea/vomiting and peripheral neuropathy, all of which were moderate, reversible and did not require a dose reduction.. Chemotherapy with oxaliplatin, leucovorin and fluorouracil showed moderate antitumor activity in metastatic ESCC and was well tolerated with acceptable myelosuppression, infrequent and reversible non-hematologic toxicities in patients with ESCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

Despite the importance of UDP-glucuronosyltransferase (UGT) 1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with folic acid (leucovorin), fluorouracil (5-FU), and irinotecan (camptosar)-based regimens. The relationships between UGT1A candidate markers across the gene (n = 21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 3'untranscribed region (3'UTR) of the UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Several functional UGT1A variants, including UGT1A1*28, significantly influenced risk of severe hematologic toxicity. As previously reported in the Italian cohort, a 5-marker risk haplotype [haplotype II (HII); UGTs 1A9/1A7/1A1] was associated with severe neutropenia in our cohort [odds ratio (OR) = 2.43; P = 0.004]. The inclusion of a 3'UTR single-nucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR = 0.55; P = 0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 3'UTR SNP allowed the identification of a protective HI (OR = 0.50; P = 0.048) and two risk haplotypes, HII and HIII, characterized by 2 and 3 unfavorable alleles, respectively, revealing a dosage effect (ORs of 2.15 and 5.28; P ≤ 0.030). Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing.

Topics: 3' Untranslated Regions; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Genetic Markers; Glucuronosyltransferase; Haplotypes; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Polymorphism, Single Nucleotide; Prospective Studies; Severity of Illness Index

This study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m2 given over 90 min i.v. and l-leucovorin 200 mg/m2 given over 120 min on day 1, followed by 5-FU 400 mg/m2 bolus and then 2400 mg/m2 infused over 46 h) in untreated metastatic colorectal cancer (mCRC).. In this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1-6. Efficacy was a secondary objective.. Thirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n=1), grade 4 neutropenia (n=4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n=1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5-79.7).. The MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Indoles; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Pyrroles; Sunitinib

Colorectal cancer (CRC) is the second most common malignancy in Japan. Inhibition of vascular endothelial growth factor (VEGF) signaling is a clinically validated therapeutic strategy in patients with metastatic CRC. Cediranib is an oral, highly potent VEGF signaling inhibitor of all three VEGF receptors.. This Phase I study investigated the safety, tolerability and pharmacokinetics of cediranib (20 or 30 mg) in combination with mFOLFOX6 in Japanese patients with previously untreated metastatic CRC. If the safety of the 20 mg dose was confirmed, a second cohort of patients was to be recruited to receive cediranib 30 mg + mFOLFOX6.. Six patients received cediranib 20 mg + mFOLFOX6 and seven received cediranib 30 mg + mFOLFOX6. One patient in the initial cediranib 20 mg cohort experienced a dose-limiting toxicity (DLT; grade 3 bilirubin increase); no DLTs were observed in the 30 mg cohort. The most commonly reported adverse events were diarrhea, decreased appetite, peripheral neuropathy, hypertension and fatigue. Two patients in the 20 mg cohort and three in the 30 mg cohort experienced serious adverse events during all treatment courses. Cediranib was generally well tolerated in this patient population with no evidence to suggest any significant pharmacokinetic interactions between cediranib and fluorouracil or oxaliplatin. A preliminary evaluation showed that five of nine evaluable patients achieved a best response of partial response.. Cediranib (20 or 30 mg) in combination with mFOLFOX6 was considered tolerable according to the protocol-defined criteria, providing justification for the Phase II part of this study.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asian People; Cohort Studies; Colorectal Neoplasms; Demography; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Quinazolines; Treatment Outcome

We investigated whether circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) patients.. In a substudy of the randomized phase II FNCLCC ACCORD 13/0503 trial, CECs (CD45- CD31+ CD146+ 7-amino-actinomycin- cells) were enumerated in 99 patients by four-color flow cytometry at baseline and after one cycle of treatment. We correlated CEC levels with objective response rate (ORR), 6-month progression-free survival (PFS) rate (primary end point of the trial), PFS, and overall survival (OS). Multivariate analyses of potential prognostic factors, including CEC counts and Köhne score, were carried out.. By multivariate analysis, high baseline CEC levels were the only independent prognostic factor for 6-month PFS rate (P < 0.01) and were independently associated with worse PFS (P = 0.02). High CEC levels after one cycle were the only independent prognostic factor for ORR (P = 0.03). High CEC levels at both time points independently predicted worse ORR (P = 0.025), 6-month PFS rate (P = 0.007), and PFS (P = 0.02). Köhne score was the only variable associated with OS.. CEC levels at baseline and after one treatment cycle may independently predict ORR and PFS in mCRC patients starting first-line bevacizumab and chemotherapy.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cell Count; Colorectal Neoplasms; Deoxycytidine; Endothelial Cells; Endothelium, Vascular; Female; Flow Cytometry; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Prognosis; Randomized Controlled Trials as Topic; Treatment Outcome

FOLFIRI is a standard chemotherapy regimen for the treatment of metastatic colorectal cancer. Although some studies have shown its efficacy in combination with bevacizumab as first-line chemotherapy, there are no data to support FOLFIRI plus bevacizumab as second-line chemotherapy in patients with this form of cancer. The aim of this study was to evaluate the efficacy and safety of FOLFIRI and bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer.. Eligible patients were ≥20 years old, previously treated (except with irinotecan [CPT-11] and bevacizumab), with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate organ function. Twenty-five eligible patients received FOLFIRI with bevacizumab at a dose of 10 mg/kg given intravenously on day 1. All therapy was administered every 2 weeks until disease progression. The primary endpoint was the response rate.. Twenty-five patients were enrolled between February 2008 and March 2009. The median age was 62 (range 38-73) years, the male/female distribution was 20/5, 16 patients had performance status 0 and 9 had performance status 1, and the proportion of patients who were oxaliplatin pretreated/untreated was 16/9. The overall response rate was 32% (90% confidence interval [CI]: 17.0-50.4%), with 8 patients showing partial responses, 15 with stable disease, and 2 with disease progression. Median progression-free survival was 11.6 months (95% CI: 6.9-16.4). Median overall survival was 21.4 months (95% CI: 12.0-30.8). The grade 3/4 adverse events with treatment were neutropenia (64%), leukopenia (16%), diarrhea (8%), anorexia (8%), and febrile neutropenia (8%). The bevacizumab-related grade 3/4 adverse event was hypertension, which was observed in 12% of patients.. The FOLFIRI plus bevacizumab regimen is an active, well-tolerated second-line chemotherapy treatment for patients with metastatic colorectal cancer.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Treatment Outcome

Symptoms and complications of metastatic colorectal cancer (mCRC) differ by metastatic sites. There is a paucity of prospective survival data for patients with peritoneal carcinomatosis colorectal cancer (pcCRC). We characterized outcomes of patients with pcCRC enrolled onto two prospective randomized trials of chemotherapy and contrasted that with other manifestations of mCRC (non-pcCRC).. A total of 2,095 patients enrolled onto two prospective randomized trials were evaluated for overall survival (OS) and progression-free survival (PFS). A Cox proportional hazard model was used to assess the adjusted associations.. The characteristics of the pcCRC group (n = 364) were similar to those of the non-pcCRC patients in median age (63 v 61 years, P = .23), sex (57% males v 61%, P = .23), and performance status (Eastern Cooperative Oncology Group performance status 0 or 1 94% v 96%, P = .06), but differed in frequency of liver (63% v 82%, P < .001) and lung metastases (27% v 34%, P = .01). Median OS (12.7 v 17.6 months, hazard ratio [HR] = 1.3; 95% CI, 1.2 to 1.5; P < .001) and PFS (5.8 v 7.2 months, HR = 1.2; 95% CI, 1.1 to 1.3; P = .001) were shorter for pcCRC versus non-pcCRC. The unfavorable prognostic influence of pcCRC remained after adjusting for age, PS, liver metastases, and other factors (OS: HR = 1.3, P < .001; PFS: HR = 1.1, P = .02). Infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, and fluorouracil as a first-line treatment among pcCRC (HR for OS = 0.62, P = .005) and non-pcCRC patients (HR = 0.66, P < .001).. pcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations of mCRC. Future trials for mCRC should consider stratifying on the basis of pcCRC status.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Peritoneal Neoplasms; Prospective Studies

Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC).. Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m(2) intravenously [IV], 5-fluorouracil 400-mg/m(2) bolus, 5-fluorouracil 2400 mg/m(2) IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events.. Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84-2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin-related death occurred because of arrhythmia.. Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Fluorouracil; Humans; Indoles; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Placebos; Retreatment

To compare the efficacy and safety of CAPIRI+bevacizumab (Bev) in comparison with FOLFIRI+Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC).. Patients were randomised to receive either FOLFIRI plus Bev 5 mg kg(-1) every 2 weeks (Arm-A) or CAPIRI plus Bev 7.5 mg kg(-1) every 3 weeks (Arm-B).. Three hundred thirty-three patients (Arm-A=167; Arm-B=166) were enrolled into the study. No difference was observed in median progression-free survival (PFS) (10.0 and 8.9 months; P=0.64), overall survival (25.7 and 27.5 months; P=0.55) or response rates (45.5 and 39.8.7%; P=0.32) for FOLFIRI-Bev and CAPIRI-Bev, respectively. Patients treated with CAPIRI-Bev presented significantly higher incidence of diarrhoea (P=0.005), febrile neutropenia (P=0.003) and hand-foot skin reactions (P=0.02) compared with patients treated with FOLFIRI-Bev. Treatment delays (P=0.05), dose reduction (P<0.001) and treatment discontinuation owing to toxicity (P=0.01) occurred more frequently in the CAPIRI-Bev arm.. The PFS of FOLFIRI-BEV is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Greece; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Treatment Outcome

Using the recommended doses obtained from our previous phase 1 trial of a modified Saltz chemotherapy regimen for metastatic colorectal cancer (weekly irinotecan and bolus 5-fluorouracil/l-leucovorin for 3 weeks every 28 days), we performed the present phase 2 trial to evaluate efficacy and toxicity.. A total of 29 patients with metastatic colorectal cancer were included. Our modified Saltz regimen was administered. The primary endpoint was overall response rate.. Of the 29 patients, 11 had previous chemotherapy. A partial response occurred in 11 patients, stable disease in 16 patients, and progressive disease in two patients. Disease control rate was 93.1%. Response rates with and without previous treatment were 18.2% and 50%, respectively. Median progression-free survival was 17.3 months. The main hematologic toxicities were leukopenia (22.6%) and neutropenia (45.2%). No treatment-related deaths occurred.. Our modified Saltz regimen exhibited sufficient efficacy, feasibility, and manageable toxicity as a therapeutic option for selected colorectal cancer patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Vitamin B Complex

This prospective phase II trial aims to evaluate the sequential FOLFOX-6 and gemcitabine followed by adapted maintenance for advanced pancreatic cancer. Treatment included FOLFOX-6 for 4 cycles, followed sequentially by gemcitabine for 3 cycles. Patients, who show clinical benefit after both sequences, will receive maintenance treatment based on the investigator's discretion. From January 2005 to June 2008, 32 patients with median age of 63 were included; 75% of patients had metastatic disease, 81% had pure adenocarcinoma, while 19% had adenocarcinoma with a neuroendocrine component. There were 22% PR and 22% SD resulting in 44% tumor growth control. Under FOLFOX, grade 3/4 toxicities were neutropenia in 8 patients, thrombocytopenia and anemia in 3 patients each, and diarrhea in 2 patients. Under Gem, grade 3/4 neutropenia was observed in 4 patients, thrombocytopenia and anemia were observed in 2 patients, and hand-foot syndrome was observed in 3 patients. The median TTP and OS were 4 and 10 months, respectively. In APC, FOLFOX-6 regimen followed by gemcitabine achieved an interesting RR within a tolerable level of toxicity. This regimen seems to warrant further investigation to confirm its efficacy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Pancreatic Neoplasms; Prospective Studies

This study aimed at assessing the efficacy and safety of biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX regimen) in patients with advanced small bowel adenocarcinoma (SBA). Thirty-three eligible patients with previously untreated SBA received 85 mg/m(2) of oxaliplatin intravenously over a 2-h period on day 1, together with 400 mg/m(2) of leucovorin over 2 h, followed by a 46-h infusion of 5-FU 2600 mg/m(2) every 2 weeks. All patients were evaluable for efficacy and toxicity. A median of nine cycles (range 3-18) was administered. The objective response rate was 48.5% [95% confidence interval (95% CI): 31-67%], with one complete response, 15 partial responses, 12 stable diseases, and five progressions. The median time to progression was 7.8 months (95% CI: 6.0-9.6) and the median overall survival was 15.2 months (95% CI: 11.0-19.4). Toxicity was fairly mild. Grade 3 toxicities included neutropenia (12.1%), thrombocytopenia (3.0%), nausea (6.1%), vomiting (3.0%), diarrhea (3.0%), peripheral neuropathy (9.1%), and fatigue (3.0%), and grade 4 toxicities occurred in none of the patients. The modified FOLFOX regimen is highly active and well tolerated as first-line chemotherapy for advanced SBA patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Duodenal Neoplasms; Female; Fluorouracil; Humans; Ileal Neoplasms; Jejunal Neoplasms; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

This phase II, open-label, single-arm study investigated sunitinib + FOLFIRI in Japanese patients with treatment-naïve unresectable/metastatic colorectal cancer. Patients received i.v. FOLFIRI (levo-leucovorin 200 mg/m(2) + irinotecan 180 mg/m(2), followed by 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) 46-h infusion) every 2 weeks, and oral sunitinib 37.5 mg/day on Schedule 4/2 (4 weeks on, 2 weeks off), until disease progression or treatment withdrawal. Progression-free survival (PFS) was the primary endpoint, with a target median of 10.8 months (35% improvement over FOLFIRI alone). Seventy-one patients started a median of 3 (range 1-11) sunitinib cycles (median relative dose intensity, <60%). The median PFS was 6.7 months (95% confidence interval, 4.7-9.2) by independent review, 7.2 months (95% confidence interval, 5.4-9.5) by investigator assessment. Objective response rate (complete responses + partial responses) was 36.6% (independent review) and 42.3% (investigator assessment). Clinical benefit rate (complete responses + partial responses + stable disease) was 83.1% (independent review) and 88.7% (investigator assessment). Common all-causality, any-grade, adverse events were: neutropenia and leukopenia (both 97.2%); thrombocytopenia (84.5%); diarrhea and nausea (both 78.9%); decreased appetite (74.6%); and fatigue (66.2%). Neutropenia (96%) was the most frequent grade 3/4 adverse event. This study was closed early due to findings from a concurrent phase III study of sunitinib + FOLFIRI in non-Japanese patients with metastatic colorectal cancer. In conclusion, the median PFS for sunitinib + FOLFIRI in Japanese patients was shorter than the 10.8 month target, indicating that sunitinib did not add to the antitumor activity of FOLFIRI. This study was registered with www.ClinicalTrials.gov (NCT00668863).

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asian People; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Indoles; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pyrroles; Sunitinib; Treatment Outcome

Leucovorin Sodium (LV/Na) has a high solubility, and is stable when given with continuous infusion of 5-FU. It could maintain significant plasma concentration of 5, 10-meTHF during the whole 5-FU perfusion with the potential of increasing 5-FU cytotoxicity. We conducted a randomized phase II clinical trial on leucovorin calcium (LV/Ca) and LV/Na in metastatic colorectal cancer patients (mCRC). Main objectives were to assess efficacy and safety.. Fifty seven patients with mCRC and no previous chemotherapy for metastatic disease were randomized to receive LV/Na or LV/Ca with irinotecan or oxaliplatine combined with infusional 5-FU. LV/Na was defined as warranting further evaluation in phase III if true overall response rate (ORR) > 35% (α=5%, β=10% in case of true ORR >55%, 51 evaluable patients planned/arm).. Results for LV/Ca and LV/Na arm respectively were: observed ORR, 55% (significantly higher than 35%, p = 0.02) and 61% (p = 0.004). Median overall survival durations were 11.9 months and 22.9 months (p = 0.02) and PFS 8.0 vs. 11.5 months (ns). Grade 3 events were 64% and 46% (p = 0.28).. Both LV/Na and LV/Ca disclosed an ORR > 35% with comparable safety.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

Bevacizumab has been extensively investigated in combination with various standard chemotherapies in the treatment of metastatic colorectal cancer (mCRC). However, a comparison to irinotecan + infusional 5-fluorouracil/leucovorin (FOLFIRI) is lacking.. To explore clinical effectiveness and cost-effectiveness of adding bevacizumab to a regimen of FOLFIRI for the first-line treatment of mCRC in the Republic of Korea by conducting an indirect treatment comparison.. A health-economic model was developed to investigate the possible health outcomes (life-years gained [LYG]), direct costs, and incremental cost-effectiveness ratio (ICER) of adding bevacizumab to a FOLFIRI regimen. Data on progression-free and overall survival were derived from randomized clinical trials and were used in the indirect treatment comparison. The annual discount rate for costs and outcomes was 5%. A lifetime horizon of 8 years was used. Sensitivity analyses were carried out on all pivotal model assumptions.. Incremental mean overall survival among patients treated with bevacizumab + FOLFIRI varied between 8.6 and 15.7 months compared with patients treated with FOLFIRI alone. The deterministic base-case result was 1.177 LYG. The discounted ICERs ranged from μ31.8 to μ39.5 million/LYG, with the base-case result being μ34.5 million/LYG. Treatment effect had the most impact on the outcomes in this model.. Although there is no formal threshold for ICER per LYG in Korea, funding may be considered for bevacizumab + FOLFIRI, particularly if the severity and end-of-life nature of mCRC is taken into account.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Cost-Benefit Analysis; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Republic of Korea

Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer.. A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival.. Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis.. Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chronotherapy; Circadian Clocks; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Sex Factors; Survival Rate; Treatment Outcome

The aim was to compare two standard chemotherapy regimens combined with bevacizumab as first-line treatment in patients with metastatic colorectal cancer.. Patients previously untreated for metastatic disease were randomized in: group A (irinotecan, capecitabine, bevacizumab, every 3 weeks; XELIRI-bevacizumab) and group B (irinotecan, leucovorin, fluorouracil, bevacizumab, every 2 weeks; FOLFIRI-bevacizumab). Primary endpoint was progression-free survival (PFS). Plasma concentrations of nitric oxide, osteopontin, TGF-β1 and VEGF-A were measured at baseline and during treatment.. Among 285 eligible patients, 143 were randomized to group A and 142 to group B. Fifty-five patients (38.5%) in group A and 57 (40.1%) in group B responded (p = 0.81). After a median follow-up of 42 months, median PFS was 10.2 and 10.8 months (p = 0.74), while median OS was 20.0 and 25.3 months (p = 0.099), for groups A and B, respectively. Most frequent grade 3-4 toxicities (group A vs group B) were neutropenia (13% vs 22%, p = 0.053) and diarrhea (19% vs 11%, p = 0.082). Baseline plasma osteopontin concentrations demonstrated prognostic significance for both PFS and OS.. This trial did not show significant differences in efficacy between the groups. However, the toxicity profile was different. Baseline plasma osteopontin concentrations demonstrated independent prognostic significance. (. ACTRN12610000270011).

Topics: Adult; Aged; Aged, 80 and over; Angiogenic Proteins; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Osteopontin; Treatment Outcome

Major concerns surround combining chemotherapy with bevacizumab in patients with colon cancer presenting with an asymptomatic intact primary tumor (IPT) and synchronous yet unresectable metastatic disease. Surgical resection of asymptomatic IPT is controversial.. Eligibility for this prospective, multicenter phase II trial included Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, asymptomatic IPT, and unresectable metastases. All received infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) combined with bevacizumab. The primary end point was major morbidity events, defined as surgical resection because of symptoms at or death related to the IPT. A 25% major morbidity rate was considered acceptable. Secondary end points included overall survival (OS) and minor morbidity related to IPT requiring hospitalization, transfusion, or nonsurgical intervention.. Ninety patients registered between March 2006 and June 2009: 86 were eligible with follow-up, median age was 58 years, and 52% were female. Median follow-up was 20.7 months. There were 12 patients (14%) with major morbidity related to IPT: 10 required surgery (eight, obstruction; one, perforation; and one, abdominal pain), and two patients died. The 24-month cumulative incidence of major morbidity was 16.3% (95% CI, 7.6% to 25.1%). Eleven IPTs were resected without a morbidity event: eight for attempted cure and three for other reasons. Two patients had minor morbidity events only: one hospitalization and one nonsurgical intervention. Median OS was 19.9 months (95% CI, 15.0 to 27.2 months).. This trial met its primary end point. Combining mFOLFOX6 with bevacizumab did not result in an unacceptable rate of obstruction, perforation, bleeding, or death related to IPT. Survival was not compromised. These patients can be spared initial noncurative resection of their asymptomatic IPT.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Female; Fluorouracil; Gastrointestinal Hemorrhage; Humans; Intestinal Obstruction; Intestinal Perforation; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Genes, ras; Germany; Humans; Leucovorin; Mutation; Neoplasm Metastasis

Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemotherapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer] assessed infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX) with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC).. Eligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day) or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies (HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]), the 20-mg dose met the predefined criteria for continuation. Subsequent patients were randomly assigned 2:1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall survival (OS) were coprimary end points.. In all, 860 patients received cediranib 20 mg (n = 502) or placebo (n = 358). The addition of cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73 to 0.98; P = .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P = .5707; median OS, 19.7 months for cediranib v 18.9 months for placebo). There were no significant differences in the secondary end points of objective response rate, duration of response, or liver resection rate. Median chemotherapy dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse events (AEs) associated with cediranib were manageable. CONCLUSION Addition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no significant difference in OS. The cediranib AE profile was consistent with those from previous studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen cannot be recommended as a treatment for patients with mCRC.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brazil; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Proportional Hazards Models; Pyridines; Quinazolines; Survival Analysis

Tumor vascular endothelial growth factor (VEGF) is a key angiogenic factor and may have an impact on tumor progression and response to chemotherapy. The insulin-like growth factor (IGF) system is related to cell proliferation and tumor growth. However, there is limited available data regarding the clinical and prognostic significance of VEGF or IGF-1 in advanced gastric cancer. The aim of this study was to evaluate the prognostic significance of serum VEGF and IGF-1 levels in advanced gastric cancer patients who were treated with oxaliplatin/5-fluorouracil (FOLFOX).. The study population consisted of 100 advanced gastric cancer patients (median age 56 years). Patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1 plus leucovorin 20 mg/m(2) over 10 min, followed by a 5-fluorouracil (5-FU) bolus 400 mg/m(2) and 22 h of continuous infusion of 600 mg/m(2) on days 1-2. Treatment was repeated in 2-week intervals. The levels of serum VEGF and IGF-1 were measured using enzyme-linked immunoassays.. There was a significant correlation between the serum level of VEGF and Lauren's classification (p = 0.030) and previous operations (p = 0.010). IGF-1 was associated with the number of metastases (p = 0.012). The median level of serum VEGF was decreased after FOLFOX chemotherapy (p = 0.034). However, none of the measured serum markers were significantly correlated with response. In univariate analysis, overall survival (p < 0.001) was significantly shorter in patients with high serum levels of VEGF. Multivariate analysis revealed that VEGF was an independent factor for overall survival (HR 2.221; 95% CI 1.377-3.583, p = 0.001). Furthermore, IGF-1 had no significant influence on the clinical outcome.. A high level of serum VEGF is an independent prognostic factor in patients with advanced gastric cancer treated with chemotherapy. This may help to identify the patients who are more sensitive to the FOLFOX regimen.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Fluorouracil; Humans; Insulin-Like Growth Factor I; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Stomach Neoplasms; Survival Rate; Treatment Outcome; Vascular Endothelial Growth Factor A

To evaluate a new strategy of two sequential, intensified chemotherapy regimens in metastatic gastric cancer.. Chemo-naïve patients with metastatic gastric cancer were enrolled to receive 4 cycles of TCF-dd (docetaxel initially 85 mg/m(2) and cisplatin initially 75 mg/m(2) on day 1 [later modified due to toxicity: 70 and 60 mg/m(2) respectively], l-folinic acid 100 mg/m(2) on days 1 and 2, 5-fluorouracil 400 mg/m(2) bolus and then 600 mg/m(2) as a 22 h continuous infusion on day 1 and 2, every 14 days). Subsequently, patients with CR, PR or SD received 4 cycles of COFFI (oxaliplatin 85 mg/m(2), irinotecan 140 mg/m(2), l-folinic acid 200 mg/m(2), 5-fluorouracil bolus 400 mg/m(2) on day 1 followed by 2,400 mg/m(2) as a 48 h continuous infusion, every 14 days). In both regimens pegfilgrastim 6 mg subcutaneously on day 3 was included.. Forty consecutive patients were enrolled. TCF-dd regimen achieved an ORR of 55% (95% CI, 40-70). Twenty-three patients proceeded to COFFI. After this regimen the ORR was then increased to 60% (95% CI, 45-75). Among the 21 patients treated with TCF-dd after the protocol amendments, main grade 3-4 toxicities were: neutropenia (29%), thrombocytopenia (19%), asthenia (24%) and diarrhea (14%). COFFI caused grade 3-4 neutropenia (all not febrile) and diarrhea in 35% and 17% of patients respectively.. A sequential strategy with TCF-dd followed by COFFI is very active and may be of special interest in selected patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Docetaxel; Dose-Response Relationship, Drug; Female; Filgrastim; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Polyethylene Glycols; Recombinant Proteins; Stomach Neoplasms; Taxoids; Treatment Outcome

Circadian rhythm disruption was linked to high serum levels of Transforming Growth Factor Receptor α, an Epidermal Growth Factor Receptor (EGFR) ligand and poor survival in patients with metastatic colorectal cancer (mCRC). We hypothesized that EGFR blockade with cetuximab would enhance the activity of chronotherapy as a result of improved circadian coordination.. All the patients with mCRC referred to our unit for progression on prior chemotherapy over a 30-month-period received weekly cetuximab and fortnightly chronotherapy.. Fifty-six patients were treated with a median of six courses of fluoropyrimidine-based chemotherapy and irinotecan (61%), oxaliplatin (25%) or both (14%) after a median of three prior regimens. We found no EFGR amplification by FISH in the tumor of 27 consecutive patients. Acneiform rash and diarrhea were the most common toxicities. Objective response rate was 32.1% and positively correlated with rash grade (p = 0.025). None of the responders had K-Ras mutation in their tumor. Median progression-free and overall survival were 4.6 and 13.7 months, respectively. Complete macroscopic resections of metastases in liver, lung or other abdominopelvic sites were performed following tumor downstaging by the treatment regimen in 11 patients (21%), 8 of whom being alive at 3 years. These figures are twice as high as those reported for first-line combination of cetuximab with conventional chemotherapy or for third line chronotherapy.. The addition of cetuximab to chronotherapy allowed safe and effective therapeutic control of metastases, including their complete resection, despite previous failure of several treatment regimens.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Drug Chronotherapy; ErbB Receptors; Female; Fluorouracil; Gene Amplification; Genes, ras; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Salvage Therapy; Survival Rate; Treatment Outcome

A regimen consisting of 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) is widely used in France in the first-line treatment of metastatic colorectal cancer (MCRC). The aim of our study was to demonstrate the non-inferiority of capecitabine plus oxaliplatin (XELOX) versus FOLFOX-6 for this indication. Patients were randomly assigned to receive XELOX or FOLFOX-6 for 6 months. The primary endpoint was overall response rate (ORR) in the per-protocol (PP) population; however, progression-free and overall survival (OS), time to response and response duration were also assessed. A total of 306 patients were enrolled (XELOX n = 156; FOLFOX-6 n = 150). ORR was 42 and 46% with XELOX and FOLFOX-6, respectively, in the PP population. The difference between groups was 4.7%; the upper limit of the unilateral 95% confidence interval (14.4%) was below the non-inferiority margin of 15%. In the intent-to-treat population, median progression-free survival was 8.8 months with XELOX and 9.3 months with FOLFOX-6, and median OS was 19.9 and 20.5 months, respectively. XELOX patients had significantly more grade 3/4 thrombocytopenia (12% vs. 5%) and diarrhoea (14% vs. 7%), but significantly less grade 3/4 neutropenia (5% vs. 47%), febrile neutropenia (0% vs. 6%) and neuropathy (11% vs. 26%) than FOLFOX-6 patients. We conclude that XELOX is non-inferior in terms of efficacy to FOLFOX-6 in the first-line treatment of MCRC, but has a different toxicity profile.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Treatment Outcome; Young Adult

Both docetaxel-based and irinotecan-based chemotherapy has been demonstrated as active combination regimen in either first-line or second-line setting for metastatic gastric cancer. The purpose of this trial was to evaluate the two active regimens, docetaxel/cisplatin and FOLFIRI, as first- and second-line chemotherapy and to compare the sequence of the two regimens in terms of efficacy and tolerability.. Eligible patients were randomized to receive one of the two treatment arms: Arm A-DP (docetaxel 75 mg/m(2) D1, cisplatin 75 mg/m(2) D1 repeated every 3 weeks) until progression or unacceptable toxicity as the first-line treatment which was followed by FOLFIRI (irinotecan 150 mg/m(2) D1, leucovorin 100 mg/m(2) D1, 5-fluorouracil 3,000 mg/m(2) D1-2 for 48 h every 2 weeks) upon disease progression as second-line chemotherapy; Arm B-FOLFIRI as the first-line treatment until disease progression or unacceptable toxicity then followed by DP as the second-line treatment upon documented disease progression.. Between April 2005 and Aug 2008, 58 patients were enrolled (Arm A, n = 28; Arm B, n = 30). Median follow-up was 38.2 months. The overall response rate (ORR) of the first-line chemotherapy was 25.0% with DP (Arm A1) and 13.3 with FOLFIRI (Arm B1) (P = 0.322). The tumor control rate (TCR) of first-line chemotherapy was 82.1% with DP and 66.7% with FOLFIRI (P = 0.209). The median first progression-free survival (1st PFS) was 4.3 months with DP and 3.4 months with FOLFIRI (P = 0.547). The overall response rate of second-line chemotherapy was 20.0% with FOLFIRI (Arm A2) and 27.2% with DP (Arm B2) (P = 0.296). The tumor control rate of second-line chemotherapy was 46.7% with FOLFIRI and 50.0% with DP. The median second progression-free survival (2nd PFS) was 8.1 months with Arm A and 6.7 months with Arm B (P = 0.865). The median overall survival was 12.5 months (95% CI 8.17-16.83) in Arm A and 13.4 months (95% CI 9.99-16.81) in Arm B (P = 0.674). In safety profile, the incidence of neutropenic fever was comparable among the 4 arms ranging from 0 to 3.9%.. The ORR, TCR of Arm A (DP → FOLFIRI) were not different from those of Arm B (FOLFIRI → DP). There was no statistically significant difference in 1st PFS, 2nd PFS, and OS of both arms. Although the trial was terminated early due to poor patient accrual, we found that both DP and FOLFIRI regimens were tolerable with comparable efficacies regardless of the sequence administered.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Stomach Neoplasms; Survival Rate; Taxoids; Treatment Outcome

The objective of the study is to investigate whether multiple chemotherapeutic agent-related genetic polymorphisms are associated with the clinical outcomes of Taiwanese metastatic colorectal cancers (mCRC) patients treated with the first-line FOLFOX-4 chemotherapy.. Consecutive mCRC patients were prospectively enrolled into this study. Peripheral blood samples were used for genotyping of polymorphisms in MTHFR, DPD, GSTP1, MDR1, TYMS, ERCC1, XRCC1, and ERCC2 genes by polymerase chain reaction-restriction fragment length polymorphism technique and DNA sequencing. The primary end point of the study was to investigate the association of each genetic polymorphism with progression-free survival and overall survival (OS).. Favorable genotypes from polymorphisms in ERCC1 codon 118C/C [hazard ratio (HR)=0.061, 95% confidence interval (CI): 0.014-0.274, P<0.001] and XRCC1 codon 399G/G (HR=0.306, 95% CI: 0.103-0.905, P=0.032) that are associated with progression-free survival were identified. Furthermore, ERCC1 codon 118C/C (HR=0.065, 95% CI: 0.011-0.377, P=0.002) and XRCC1 codon 399G/G (HR=0.152, 95% CI: 0.041-0.568, P=0.005) were significantly associated with favorable OS. Combining ERCC1 and XRCC1 genetic polymorphisms, patients with both favorable genotypes of ERCC1 codon 118C/C and XRCC1 codon 399G/G were associated with the better OS than those with one or without any favorable genotypes (P<0.001).. The genetic polymorphisms of ERCC1 and XRCC1 may be useful in predicting clinical outcome in Taiwanese mCRC patients treated with FOLFOX-4. However, further prospective studies will be needed for the potential clinical implication.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Genetic Association Studies; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Polymorphism, Genetic; Prognosis; Taiwan; Treatment Outcome

The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC).. Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF: -2578A/C, -1498C/T, -1154A/G, -634C/G and 936C/T; and VEGFR-2: -604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients.. Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found.. Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neovascularization, Pathologic; Organoplatinum Compounds; Pharmacogenetics; Thrombospondin 1; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

To compare the pharmacokinetics (PK) of bevacizumab (BV) at steady-state under two different dosing regimens, 7.5 mg/kg q3w and 5.0 mg/kg q2w, concomitantly with a combination of capecitabine and oxaliplatin (XELOX) and FOLFOX-4 (oxaliplatin in combination with infusional 5-FU/LV), respectively, in patients with metastatic colorectal cancer (mCRC).. Patients were randomized in a 1:1 ratio to either XELOX + BV or FOLFOX-4 + BV. Blood samples for steady-state PK of BV were collected on day 1 of cycle 5 (at the earliest) for XELOX + BV treatment and day 1 of cycle 7 (at the earliest) for FOLFOX-4 + BV treatment.. A total of 64 patients were enrolled, of which 37 were eligible for PK analyses. The primary PK parameter of BV, AUC(ss(per week)), was statistically similar between the two dosing regimens with the 90% confidence interval in the commonly used no-effect boundaries of 0.8 and 1.25. The V (ss) and CL did not differ between the two regimens; t (½) during the PK cycle was also similar for both arms at approximately 16 days. These results demonstrated no clinically relevant change in BV PK when co-administered with either XELOX or FOLFOX-4. BV in combination with XELOX and FOLFOX-4 was generally well tolerated with no unexpected safety signals and no deaths. Nine patients in the XELOX + BV arm and 15 patients in the FOLFOX-4 + BV arm experienced at least one SAE (most commonly gastrointestinal disorders) which led to dose modification in 7 and 2 patients, respectively, and to premature withdrawal in 9 and 5 patients, respectively. All 64 patients experienced at least one non-serious AE. Laboratory tests and vital signs were unremarkable.. No clinically relevant differences in overall steady-state exposure of BV occurred when BV was given 7.5 mg/kg q3w in combination with XELOX or 5.0 mg/kg q2w with FOLFOX-4 in patients with mCRC, and the pharmacokinetics of BV were very similar between the two regimens. No unexpected adverse events or deaths were identified.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

To evaluate the efficacy and safety of FOLFOX4 using "wait and go" strategy in treating metastatic colorectal cancer.. The conventional FOLFOX4 was repeated every 2 weeks. We waited until the recovery of symptoms from persistent neurotoxicity within an added period of 2 weeks, before performing the next cycle ("wait and go" strategy).. We enrolled 58 patients, in whom a total of 481 cycles were administered (median 8 per patient; range 1-16). Toxicity was evaluated in 58 patients and response in 55. The major toxic effect was grade 3/4 neutropenia (33%). Painful paresthesia or persistent functional impairment was observed in 4 patients (7%). The response rate was 40% (95% confidence interval; 27.1-52.9%). The median progression-free survival time was 10.2 months, the 1-year survival rate was 89%, and the median overall survival time was 27.6 months.. These findings indicate that this "wait and go" strategy reduces the frequency of persistent neuropathy while maintaining efficacy against metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

A combination of fluorouracil and leucovorin (5-FU/LV) with oxaliplatin (FOLFOX) is an established first-line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. A strategy to stop FOLFOX, deliver 5-FU/LV as a maintenance therapy and reintroduce FOLFOX was found to be equivalent in terms of efficacy while neurotoxicity was substantially reduced. The aim of this study was to evaluate feasibility of a stop-and-go strategy with S-1, an oral fluoropyrimidine derivative, as a maintenance therapy administered between modified FOLFOX6 (mFOLFOX6) as a first-line treatment of mCRC.. Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 followed by maintenance therapy with oral S-1. Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or upon tumor progression. The primary endpoint was duration of disease control (DDC).. Twenty-one of the 30 patients who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in 15 patients. Median DDC and progression-free survival were 9.3 and 7.9 months, respectively. The response rates and disease control rates were 40.0 and 86.6% for the initial mFOLFOX6, 23.8 and 57.1% for S-1 maintenance therapy and 20.0 and 73.3% for mFOLFOX6 reintroduction, respectively. Twenty-eight patients (93.3%) had peripheral neuropathy, but grade 3 neurotoxicity was observed in only 1 patient (3.3%).. The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible as a first-line treatment for Japanese mCRC patients. Further prospective randomized control study is warranted.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

Treatment options for patients with previously treated metastatic colorectal cancer (mCRC) are limited, and treatments with differing mechanisms of action are needed. PTK787/ZK 222584 (PTK/ZK) is a novel oral angiogenesis inhibitor with therapeutic potential for the treatment of solid tumors.. Patients (N = 855) were randomly assigned to treatment with PTK/ZK or placebo once daily in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4). Stratification factors included WHO performance status (PS; 0 v 1 to 2) and lactate dehydrogenase ([LDH] ≤ 1.5× the upper limit of normal [ULN] v > 1.5 × ULN). Treatment was given until disease progression or unacceptable toxicity. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, tolerability, and pharmacokinetics of PTK/ZK.. No statistically significant differences were seen between the treatment groups for the overall comparison of OS. With PTK/ZK and placebo, respectively, median OS was 13.1 and 11.9 months (hazard ratio [HR], 1.00; 95% CI, 0.87 to 1.16; P = .957). Median PFS was longer with PTK/ZK than with placebo (5.6 and 4.2 months, respectively; HR, 0.83; 95% CI, 0.71 to 0.96; P = .013). An exploratory, post hoc analysis demonstrated improved PFS in patients with high LDH, regardless of WHO PS (HR, 0.63; 95% CI, 0.48 to 0.83; P < .001).. PTK/ZK in combination with FOLFOX4 did not improve OS of patients with pretreated mCRC but did improve PFS. The effect of PTK/ZK was more pronounced in patients with high LDH at baseline.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Phthalazines; Placebos; Pyridines

PTK787/ZK 222584 (PTK/ZK; vatalanib), an orally active, multitargeted angiogenesis inhibitor, has shown tolerability and promising activity in early-phase studies, which led to a phase III trial in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4).. Patients (N = 1,168) with previously untreated metastatic colorectal cancer were randomly assigned 1:1 to receive FOLFOX4 plus PTK/ZK or placebo (ClinicalTrials.gov identifier: NCT00056459). Stratification factors included WHO performance status (0 v 1 or 2) and serum lactate dehydrogenase (LDH; ≤ v > 1.5× the upper limit of normal). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR).. PFS, OS, and ORR were not statistically improved with PTK/ZK (P > .05). Median PFS by central review was 7.7 months with PTK/ZK versus 7.6 months with placebo (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .118); median OS was 21.4 months with PTK/ZK versus 20.5 months with placebo (HR, 1.08; 95% CI, 0.94 to 1.24; P = .260). In an exploratory post hoc analysis of PFS in patients (n = 158 per arm) with high serum LDH, a potential marker of hypoxia, PFS was longer with PTK/ZK versus placebo (7.7 v 5.8 months, respectively; HR, 0.67; 95% CI, 0.49 to 0.91; P = .009).. Although the efficacy objectives of this study were not met, a subgroup of patients who may potentially benefit from small-molecule vascular endothelial growth factor receptor inhibitor therapy has been identified and further research is warranted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Phthalazines; Placebos; Protein Kinase Inhibitors; Pyridines; Receptors, Vascular Endothelial Growth Factor

The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken.. Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series.. The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis.. The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins

Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer.. We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival.. The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001).. As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Proportional Hazards Models; Quality of Life; Severity of Illness Index; Survival Analysis

Gemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy.. In this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (<3, 3 to 6 and >6 months), performance status (KPS 70-80%; 90-100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200mg/m(2) followed by 5-fluorouracil 2g/m(2) (24h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m(2) on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy.. After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29-5.35] months for OFF treatment and 2.30 [95% CI; 1.76-2.83] months with BSC alone (0.45 [95% CI: 0.24-0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97-11.21] and 7.90 [95% CI: 4.95-10.84] months for GEM-BSC (0.50 [95% CI: 0.27-0.95], p = 0.031) respectively.. Although stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC. OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Female; Fluorouracil; Gemcitabine; Germany; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Mortality rates in published irinotecan-based trials range between 1.7% and 5.0%. This analysis aimed to evaluate clinical and histopathologic factors associated with 60-day mortality in first-line therapy for metastatic colorectal cancer (mCRC).. Sixty-day all-cause and disease-specific mortality rates from 479 patients who participated in a randomized phase III study comparing FUFIRI (5-fluorouracil [5-FU], leucovorin, irinotecan) (n = 238) vs. mIROX (modified irinotecan plus oxaliplatin (n = 241) were evaluated for association with prognostic factors such as platelet counts, alkaline phosphatase (AP) levels, white blood cell (WBC) counts, hemoglobin values, lactate dehydrogenase (LDH) levels, carcinoembryonic antigen (CEA) levels, and several other baseline parameters using univariate and multivariate logistic regression analyses applied to patients combined from both treatment groups.. The all-cause 60-day mortality rate was 5.0% (24/479). Thirteen patients (5.5%) in the FUFIRI arm died within the first 60 days of treatment compared with 11 (4.6%) patients in the mIROX arm (P = .68). Among the 24 patients in both treatment arms, mortality was qualified as disease related in 15 (63%) patients and treatment related in 7 (29%) patients (P = .695). In multivariate analyses, high LDH levels (P = .010) and an elevated WBC count (P = .006) remained as significant independent prognostic factors. Low Karnofsky performance status (KPS) showed a strong trend but failed to reach statistical significance (P = .057) as did AP levels and the number of metastatic sites.. In this study 63% of the early deaths were disease related, whereas only 29% were possibly related to study medication. Independent prognostic factors for early mortality were LDH levels and WBC counts. KPS showed a strong trend in the multivariate analysis. Future investigation may consider LDH levels and WBC counts for exclusion criteria.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate; Young Adult

There is increased recognition that cancers of the upper GI tract comprise distinct epidemiological and molecular entities. Erlotinib has shown activity in patients with adenocarcinoma of the oesophagus/gastro-oesophageal junction (GEJ), but not in distal gastric cancer. mFOLFOX6 is one of several active regimens used to treat adenocarcinoma of the Eso/GEJ. This study evaluates the efficacy and safety of mFOLFOX6 and erlotinib in patients with metastatic or advanced Eso/GEJ cancers.. Patients with previously untreated advanced or metastatic Eso/GEJ adenocarcinoma are treated with oxaliplatin 85 mg m(-2), 5-FU 400 mg m(-2), LV 400 mg m(-2) on day 1, 5-FU 2400 mg m(-2) over 48 h and erlotinib 150 mg PO daily. Treatment was repeated every 14 days. The primary objective was response rate (RR), secondary objectives include toxicity, progression-free survival (PFS), overall survival (OS) and to correlate clinical outcome with expression patterns and molecular alterations in the epidermal growth factor receptor-dependent pathways.. A total of 33 patients were treated and evaluable: there were two complete responses, 15 partial responses for an objective RR of 51.5% (95% CI, 34.5-68.6%). Median PFS was 5.5 months (95% CI, 3.1-7.5 months) and median OS was 11.0 months (95% CI, 8.0-17.4 months). The most common grade 3-4 toxicities were: diarrhoea (24%), nausea/vomiting (11%), skin rash (8%) and peripheral neuropathy (8%). The frequency of alterations was KRAS mutations (8%), EGFR mutations (0%) and HER2 amplification (19%).. In patients with Eso/GEJ adenocarcinoma, mFOLFOX6 and erlotinib is active, has an acceptable toxicity profile and FOLFOX ± erlotinib could be considered for further development.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease-Free Survival; Erlotinib Hydrochloride; Esophageal Neoplasms; Esophagogastric Junction; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Protein Kinase Inhibitors; Quinazolines

To evaluate the efficacy and safety of yiqi zhuyu decoction (YZD) combined with oxaliplatin plus 5-flurouracil/leucovorin (FOLFOX-4) in the patients with metastatic colorectal cancer (MCRC).. A total of 120 patients with MCRC were randomly divided into the experimental group (FOLFOX-4 plus YZD, 60 cases) and the control group (FOLFOX-4 plus placebo, 60 cases), according to the sequence of hospitalization from January 2005 to December 2007. The treatment was supposed to be continued until disease progression (PD) or for 48 weeks (i.e., up to 24 cycles of FOLFOX-4). Response rate (RR), progression-free survival (PFS), overall survival (OS) and adverse events (AEs) were observed.. RR was 41.5% in the experimental group and 34.0% in the control group [odds ratio (OR): 1.18, 95% CI: 0.77 to 1.82, P=0.432]. Median PFS were 9.0 months and 8.0 months, respectively [hazard ratio (HR): 0.78, 95% CI: 0.53 to 1.15, P=0.215]. Median OS were 21.0 months and 18.0 months (HR: 0.65, 95% CI: 0.43 to 0.99, P=0.043) and grade 3/4 AEs were 56.6% and 76.7% (OR: 0.61, 95% CI: 0.18 to 0.87, P=0.020), respectively.. YZD combined with FOLFOX-4 chemotherapy significantly improved OS in this first-line trial in the patients with MCRC and significantly decreased grade 3/4 AEs. However, RR was not improved, and PFS did not reach statistical significance by the addition of YZD. The treatment of YZD combined with FOLFOX-4 may be necessary in order to optimize efficacy and safety.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drugs, Chinese Herbal; Female; Fluorouracil; Humans; Intention to Treat Analysis; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Patient Dropouts; Treatment Outcome

Pancreatic endocrine carcinomas are rare and heterogeneous. Published results concerning treatment of advanced tumours are inconsistent and responses to standard chemotherapy remain unsatisfactory.. To investigate the ability of the FOLFIRI regimen to manage progressive unresectable metastatic well-differentiated endocrine carcinomas of the pancreas as first-line chemotherapy.. 20 patients with metastatic or advanced well-differentiated endocrine carcinomas of the pancreas and progressive disease were enrolled in a prospective multicentre phase II trial to receive chemotherapy with FOLFIRI schedule (irinotecan 180mg/m(2) infusion combined with simplified LV5FU2) every 14 days. The primary end point was the non-progression rate at 6 months.. The 6-month non-progression rate was 80% (95% confidence interval [56-94%]), with stabilisation in 15 patients and 1 objective response. Overall survival at 24 months was 65% [40-82%]. Median progression-free survival was 9.1 months [6.5-17.3 months]. The median number of administered cycles was 12 [range 1-28]. Grade 3/4 haematologic toxicity occurred in 5 patients (25%) and grade 3 digestive toxicity in 11.. The FOLFIRI regimen, as first-line chemotherapy, achieved stabilisation in most patients whose tumours had been progressing and was well-tolerated. It could be an alternative therapy for advanced well-differentiated endocrine carcinomas of the pancreas.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Disease-Free Survival; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Treatment Outcome

Circadian clocks control cellular proliferation and drug metabolism over the 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (chronoFLO4) offered no survival benefit as compared with the non-time-stipulated FOLFOX2, in an international randomized trial involving patients with previously untreated metastatic colorectal cancer (EORTC 05963). The authors hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Patients with available data (N = 556) were categorized into three subgroups according to the worst grade (G) of neutropenia experienced during treatment. Distinct multivariate models with time-dependent covariates were constructed for each treatment schedule. Neutropenia incidence (all grades) was 33% on chronoFLO4 and 61% on FOLFOX2 (p < .0001), and G3-4 were 7% and 25%, respectively (p < .0001). Neutropenia was significantly more frequent in women than men on either schedule (FOLFOX2, p = .003; chronoFLO4, p = .04). Median survival was 20.7 mo in patients with G3-4 neutropenia versus 12.5 mo in neutropenia-free patients on FOLFOX2 (p < .0001). Corresponding figures were 13.7 and 19.4 mo, respectively, on chronoFLO4 (p = .36). Multivariate analysis confirmed occurrence of severe neutropenia independently predicted for better overall survival on FOLFOX2 (HR = 0.56; p = .015), and worse survival on chronoFLO4 (HR = 1.77, p = .06), with a significant interaction test (p < .0001). Prediction of better survival in neutropenic patients on FOLFOX2 supports the administration of conventional chemotherapy near maximum tolerated dose. The opposite trend shown here for chronoFLO4 supports the novel concept of jointly optimized hematologic tolerability and efficacy through personalized circadian-timed therapy.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Clocks; Circadian Rhythm; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Analysis; Treatment Outcome; Young Adult

The present study was done to establish a prognostic model for patients and trials using an oxaliplatin-based or irinotecan-based first-line chemotherapy in metastatic colorectal cancer.. Eight hundred three patients treated with FOLFOX or FOLFIRI in three prospective trials were randomly separated into learning (n = 535) and validation (n = 268) samples. Eleven baseline variables were evaluated in univariate and multivariate analysis as prognostic factors for overall survival, and a prognostic score was developed.. Independent prognostic factors identified in multivariate analysis for overall survival were performance status (PS) (p < .001), serum lactate dehydrogenase (LDH) (p < .001), and number of metastatic sites (p = .005). A prognostic score based on these three variables was found efficient (Harrell's C index 0.61). This new model was improved by selecting only PS and LDH (Harrell's C index 0.64). Three risk groups for death could be identified: a low-risk group (n = 184; median overall survival [OS] 29.8 months), an intermediate-risk group (n = 223; median OS 19.5 months), and a high-risk group (n = 128; median OS 13.9 months). Median survival for the low-, intermediate-, and high-risk groups were 26.8, 21.1, and 16.5 months, respectively, in the validation sample (Harrell's C index 0.63).. Serum LDH level was the main prognostic factor in predicting survival, followed by WHO PS. We identified three risk groups for death depending on these two baseline parameters. This simple prognostic model can be useful for clinician's use and patient stratification in future clinical trials.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; L-Lactate Dehydrogenase; Leucovorin; Male; Middle Aged; Models, Statistical; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Analysis; Treatment Outcome

The efficacy and safety of bevacizumab with modified irinotecan, leucovorin bolus, and 5-fluorouracil intravenous infusion (mIFL) in the first-line treatment of metastatic colorectal cancer (mCRC) has not been well evaluated in randomized clinical trials in Chinese patients. We conducted a phrase III trial in which patients with previously untreated mCRC were randomized 2:1 to the mIFL [irinotecan (125 mg/m(2)), leucovorin (20 mg/m(2)) bolus, and 5-fluorouracil intravenous infusion (500 mg/m(2)) weekly for four weeks every six weeks] plus bevacizumab (5 mg/kg every two weeks) group and the mIFL group, respectively. Co-primary objectives were progression-free survival (PFS) and 6-month PFS rate. In total, 214 patients were enrolled. Our results showed that addition of bevacizumab to mIFL significantly improved median PFS (4.2 months in the mIFL group vs. 8.3 months in the bevacizumab plus mIFL group, P < 0.001), 6-month PFS rate (25.0% vs. 62.6%, P < 0.001), median overall survival (13.4 months vs. 18.7 months, P = 0.014), and response rate (17% vs. 35%, P = 0.013). Grades 3 and 4 adverse events included diarrhea (21% in the mIFL group and 26% in the bevacizumab plus mIFL group) and neutropenia (19% in the mIFL group and 33% in the bevacizumab plus mIFL group). No wound-healing complications or congestive heart failure occurred. Our results suggested that bevacizumab plus mIFL is effective and well tolerated as first-line treatment for Chinese patients with mCRC. Clinical benefit and safety profiles were consistent with those observed in pivotal phase III trials with mainly Caucasian patients.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Asian People; Bevacizumab; Camptothecin; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Prospective Studies; Survival Rate; Young Adult

Despite current treatment options, metastatic breast cancer (MBC) remains essentially incurable, requiring research on new drugs or combinations to improve survival and quality of life.. This phase I study was designed to define the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose of all-oral tegafur-uracil (UFT)/folinic acid combined with vinorelbine as chemotherapy for MBC. Starting doses were 40 mg/m(2)/week of oral vinorelbine administered continuously and 250 mg/m(2)/day of UFT plus 90 mg/day of folinic acid from day 1 to day 28, followed by a 1-week rest period.. Ten patients were included. Eight were evaluable for toxicity and antitumor response. The second dose level was shown to be the MTD. At this dose, 2 out of 5 patients receiving oral vinorelbine at 40 mg/m(2)/week and UFT at 300 mg/m(2)/day developed DLT consisting of grade 3 asthenia and grade 3 nausea despite standard prophylaxis. Other toxicities were grade 1 diarrhea and anemia. There were no treatment-related deaths.. The recommended dose for this combination seems to be the first dose level. A stable response was observed for 6 patients (average 33 weeks). This combination appears to be well-tolerated and offers an alternative to intravenous chemotherapy.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Leucovorin; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Tegafur; Uracil; Vinblastine; Vinorelbine

Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is used as monotherapy for chemorefractory metastatic colorectal cancer (mCRC) in patients with wild-type (WT) KRAS tumors. Although skin toxicities are the most common adverse events associated with EGFR inhibitors, the differences in efficacy and safety between pre-emptive and reactive skin treatment according to KRAS tumor status has not been reported.. Eligible patients had mCRC with disease progression or unacceptable toxicity with first-line treatment containing fluoropyrimidine and oxaliplatin-based chemotherapy ± bevacizumab. Patients were randomized 1:1 to pre-emptive or reactive skin treatment (after skin toxicity developed). Patients received either panitumumab 6 mg/kg + FOLFIRI every 2 weeks or panitumumab 9 mg/kg + irinotecan every 3 weeks. Key study endpoints included overall response rate (ORR), overall survival, progression-free survival (PFS), and safety according to KRAS tumor status.. Eighty-seven (92%) of 95 enrolled patients had evaluable KRAS tumor status: 49 (56%) patients with WT and 38 (44%) patients with mutant (MT) KRAS tumors, respectively. The ORR was 16% and 8% for patients with WT and MT KRAS tumors, respectively. Median PFS was 5.5 and 3.3 months for patients with WT and MT KRAS tumors, respectively. The most commonly observed adverse events by KRAS tumor status included dermatitis acneiform and pruritus.. Panitumumab in combination with irinotecan-based chemotherapy has an acceptable toxicity profile in second-line therapy for mCRC. Numerical differences trending in favor of the patients with WT KRAS tumors were observed for most efficacy endpoints.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; DNA, Neoplasm; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Polymerase Chain Reaction; Premedication; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Salvage Therapy; Skin Diseases; Survival Rate; Young Adult

Triplet chemotherapy has demonstrated manageable toxicities and a favorable response rate. The addition of cetuximab to chemotherapy can increase treatment efficacy. We evaluated the efficacy and safety of cetuximab plus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), the ERBIRINOX regimen, as first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC).. In a phase II study, treatment consisted of weekly cetuximab plus biweekly. Treatment was continued for a maximum of 12 cycles and tumor response was evaluated every four cycles. The primary efficacy criterion was the complete response (CR) rate.. From April 2006 to April 2008, 42 patients were enrolled. The median age was 60 years (range, 32-76 years). The median duration of treatment was 5.2 months (range, 0.7-8.5 months), and a median of nine cycles was given per patient (range, 1-12 cycles). Five patients (11.9%) showed a CR, with a median duration of 23.1 months (95% confidence interval [CI], 10.8-39.7 months). The objective response rate was 80.9% (95% CI, 65.9%-91.4%). The median overall and progression-free survival times were 24.7 months (95% CI, 22.6 months to not reached) and 9.5 months (95% CI, 7.6-10.4 months), respectively. The most frequent grade 3-4 adverse events were diarrhea (52%), neutropenia (38%), and asthenia (32%).. The ERBIRINOX regimen appears to be effective and feasible in first-line treatment of mCRC patients. These promising results led us to initiate a multicenter, randomized, phase II trial ([Research Partnership for Digestive Oncology] PRODIGE 14) in patients with potentially resectable mCRC.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate

We evaluated the efficacy and safety of bolus 5-fluorouracil (5-FU) and leucovorin combined with weekly paclitaxel (FLTAX) in advanced gastric cancer (GC) patients.. Patients with untreated stage IV GC received paclitaxel 80 mg/m(2) as a 1-hour infusion, followed by 5-FU 600 mg/m(2) as a bolus infusion and L-leucovorin 250 mg/m(2) as a 2-hour infusion on days 1, 8 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was response rate.. Thirty-five patients were enrolled. The median age was 62 years (range 34-75). Twenty-one patients (60%) had diffuse-type cancer and 11 had peritoneal metastasis. The confirmed response rate was 43% (95% CI 26-61) with 15 partial responses. Stable disease was observed in 16 (46%) patients. Median progression-free survival and overall survival were 6.8 months (95% CI 5.8-7.4) and 16.2 months (95% CI 10.0-22.8), respectively. Grade 3-4 adverse events were: neutropenia (54%), febrile neutropenia (3%), diarrhea (6%) and sensory neuropathy (11%).. FLTAX showed a desirable safety profile, and the efficacy against advanced GC was encouraging. FLTAX may be a good option for GC patients with deteriorated general condition, and a randomized clinical trial in such patients is currently underway.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Paclitaxel; Stomach Neoplasms

This is a multicenter phase II study to assess the efficacy and toxicity of the 5-FU, leucovorin, and oxaliplatin (FLOX) (SWIFT 3) regimen in Japanese patients with advanced colorectal cancer (CRC).. Fifty-two patients were enrolled and evaluated from 12 institutions. The median age was 66 years, with 40.4% of patients with colon cancer and 59.6% with rectal cancer.. Forty-one patients underwent chemotherapy for first-line therapy and 11 patients for second-line. The response rate for first-line was 46.3% and that for second-line was 9.1%. The response rates categorized by metastatic sites were 59.4% for liver, 33.3% for lung, and 22.2% for lymph nodes. Grade 3/4 neutropenia occurred in 21.2% and Grade 3/4 non-hematologic toxicity in 46.1%. There were no deaths within 60 days following the administration.. Standard FLOX regimen can be administered for Japanese patients. It is suggested that FLOX is an appropriate option for adjuvant therapy in CRC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

This phase II study was designed in order to evaluate efficacy and safety of the combination of vinorelbine (VNB), fluorouracil (FU) and leucovorin (LV) in patients with metastatic breast carcinoma (MBC) previously treated with anthracyclines and taxanes.. From 12/2003 to 12/2007, 51 women (median age 59) were treated. Performance status (PS) (ECOG) was 0-2 (median 0). The chemotherapy consisted of VNB 25 mg/sqm on day 1 added to FU and LV (following De Gramont schedule) on day 1 and 2. Treatment was repeated every 14 days. 518 cycles of CT were administered (median 12). Most common sites of metastatic spread were: bone, liver, lymph nodes, lung.. We recorded three cases of G4 neuthropenia and in one case it was febrile; no others G4 toxicities were seen. G3 toxicities were more common, especially neuthropenia (8 patients) asthenia (4) mucositis (2) and Hand-Foot Syndrome (2). Overall response rate was 27.5% (14 patients had a PR) and disease control rate was 76.5%; 12 patients experienced disease progression. Median time to progression (TTP) was 7.70 months and overall survival (OS) was 18.70 months.. Results demonstrate that the ViFL regimen has substantial activity in patients with MBC already treated with anthracyclines and taxanes. The combination may be considered a valid choice for the treatment of MBC. Better survival results were seen in patients with visceral metastases than bone involvement. The low response rate shows that the ViFL regimen is not suitable for the neoadjuvant setting.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Survival Analysis; Taxoids; Vinblastine; Vinorelbine

S-1, a novel oral fluoropyrimidine, is well tolerated in patients with metastatic colorectal cancer (mCRC). The response rate of S-1 for colorectal cancer is high, ranging from 35% to 40%. This study aimed to evaluate the safety and efficacy of S-1 combined with oral leucovorin (LV) to enhance antitumor activity in chemotherapy-naive patients with mCRC.. S-1 was given orally twice daily for two consecutive weeks at a daily dose of 80-120 mg, followed by a 2-week rest period, within a 4-week cycle. LV was given orally twice a day at a daily dose of 50 mg, simultaneously with S-1.. Of the 56 patients with previously untreated mCRC, 32 (57%) had partial responses. The median follow-up period was 27.2 months. The median time to progression was 6.7 months (95% confidence interval 5.4-7.9). The median survival time was 24.3 months. There was no treatment-related death or grade 4 toxicity. The most common grade 3 toxic effects were diarrhea (32%), anorexia (21%), stomatitis (20%), and neutropenia (14%).. S-1 combined with LV therapy demonstrated promising efficacy and acceptable safety in chemotherapy-naive patients with mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Survival Analysis; Tegafur; Treatment Outcome

Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer.. Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m(-2) at first infusion followed by weekly infusions of 250 mg m(-2) combined with FUFOX (oxaliplatin 50 mg m(-2), 5-FU 2000 mg m(-2), and DL-folinic acid 200 mg m(-2) d1, 8, 15 and 22 qd36). The primary endpoint was tumour response.. Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50-79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0-10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9-11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed.. Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum-fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Stomach Neoplasms

A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin was combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provided higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU.. Ninety-one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m(2), administered in 3 doses of 100 mg/m(2) each every 8 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival.. Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug-related > or = grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea.. The combination of UFT and leucovorin administered orally in a 3-times-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Recurrence; Retreatment; Tegafur; Uracil

UFT, a combination of uracil and ftorafur, was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin is combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provide higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU.. Ninety-four patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m(2), which was given in 2 divided doses every 12 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (OR = complete response [CR] + partial response [PR]) and overall survival (OS).. Of the 94 patients enrolled, 68 were evaluable for efficacy. Although no CRs were observed, 9 patients achieved PRs, for an OR of 13.2% in the evaluable population. The median TTP for the evaluable population was 10.3 weeks, and the proportion of patients free of disease progression at 6 months was 17%. The median OS was 61.6 weeks for all patients enrolled. The most common drug-related >or= grade 3 adverse events (graded using the National Cancer Institute Common Toxicity Criteria version 2) were diarrhea, asthenia, nausea, and dehydration.. The combination of UFT and leucovorin administered orally in a twice-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Recurrence; Tegafur; Uracil

Combined therapy with irinotecan/fluorouracil/levoleucovorin (calcium levofolinate) [IFL] has lost its position as the standard regimen for metastatic colorectal cancer because its toxicity and effectiveness have become controversial.. To (i) identify the optimal regimen for IFL therapy in terms of irinotecan dosage, and (ii) determine the maximum tolerated dose and efficacy of the modified-IFL regimen in patients with histologically confirmed advanced colorectal cancer.. In a phase I study, nine patients with advanced colorectal cancer received IFL treatment modified such that irinotecan was administered every 2 weeks, as opposed to the more toxic once-weekly administration. The study evaluated three escalating dose levels of irinotecan (100, 125 and 150 mg/m(2)). Each treatment cycle consisted of irinotecan on days 1 and 15; fluorouracil 600 mg/m(2) on days 1, 8, 15 and 22; and levoleucovorin 250 mg/m(2) on days 1, 8, 15 and 22. Data from the phase I study were used to determine the recommended dose of irinotecan for the phase II study. The latter study evaluated the effectiveness (overall response rate, median time to disease progression and median survival time) and tolerability of this modified-IFL therapy as ambulatory treatment in 22 patients with advanced colorectal cancer.. The dose-limiting toxicity of irinotecan was grade 3 neutropenia, which occurred in three patients at dose level 2 (125 mg/m(2)); furthermore, a fourth patient developed grade 4 neutropenia at this dose level. Therefore, 125 mg/m(2) was considered to be the maximum tolerated dose, and the dose of irinotecan for the phase II study was set at 100 mg/m(2). Fourteen patients achieved partial response using this modified-IFL regimen, and the overall response rate was 63.6% (95% CI 43.5, 83.7). The median time to progression was 197 days (range 111-283 days) and the median survival time was 414 days (95% CI 116, 712). Toxicities were acceptable and manageable.. Modified-IFL therapy is a practical, effective and tolerable option for ambulatory treatment of advanced colorectal cancer.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Survival Rate; Treatment Outcome; Young Adult

5-Fluorouracil (5-FU) plus cisplatin (C) can be considered a standard option for advanced gastric cancer (AGC). Irinotecan (Ir) and docetaxel (D) are active agents with no complete cross-resistance with C and 5-FU. Concomitant combination of Ir or D with C and 5-FU is feasible, but with substantial toxicities. A different way to include all active agents in first-line treatment of AGC may be to use them sequentially. We aimed to evaluate the activity and the safety profile of sequential chemotherapy with 5-FU-based doublets with C, Ir and D in the first-line treatment of AGC.. We conducted a phase II study of first-line sequential chemotherapy in metastatic GC. Treatment consisted of 3 cycles of C + infused 5-FU and leucovorin (CFL) followed by 3 cycles of Ir + 5-FU/LV (IrFL) followed by 3 cycles of D + 5-FU/LV (DFL). Primary end-point was response rate.. Forty-six patients were enrolled, median age 60 years, sites of disease (single/multiple) = 9/37, PS 0/1 = 27/19, gastric/gastro-oesophageal junction = 39/7. Median number of cycles was 9. Main grade 3-4 toxicities were neutropenia (37%), febrile neutropenia (2%), diarrhoea (4%), stomatitis (9%). Response rate after the planned 9 cycles was 45% (15 partial and 5 complete responses among 43 evaluable patients). Median PFS and OS: 6.8 and 11.1 months, respectively.. This sequential treatment is feasible with a favourable safety profile and produced encouraging results in terms of activity and efficacy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Docetaxel; Esophageal Neoplasms; Esophagogastric Junction; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Stomach Neoplasms; Taxoids; Treatment Outcome

The methionine (MET) dependency of tumor cells opens interesting perspectives for targeting tumor cells and potentiating chemotherapy treatment, like 5-fluorouracil (5-FU) and platinum compound. Since MET deprivation can individually potentiate the different chemotherapeutic agents used in the 48-hour combined regimen of 5-FU, leucovorin and oxaliplatin (FOLFOX) regimen, we initiated a feasibility study associating dietary MET restriction with the FOLFOX regimen in patients with metastatic colorectal cancer.. (i) To evaluate the depletion in the plasma MET concentration, and (ii) to assess the feasibility of this combination.. Eleven patients were enrolled in this study. They received a median number of 3 two-week cycles of a MET-free diet (3 consecutive days) and FOLFOX6 regimen.. The plasma MET concentration was reduced by dietary MET restriction, with a depletion of 58% on the 1st day of MET-free diet. Indeed, we demonstrated the feasibility and good tolerance (nutritional status and toxicity) of the association of a MET-free diet with the FOLFOX regimen. Despite good compliance to the diet, this study revealed the difficulty of administering this combination during further months. Among the 4 patients evaluable for response, 3 experienced a partial response and 1 patient a disease stabilization.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diet; Disease Progression; Feasibility Studies; Female; Fluorouracil; Humans; Leucovorin; Male; Methionine; Middle Aged; Models, Statistical; Monitoring, Physiologic; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

Breast cancer is the leading nonhematologic cause of meningeal carcinomatosis (MC). The aim of this study was to report the outcome of patients diagnosed with breast cancer MC and treated in single institution by a high-dose intrathecal methotrexate (MTX) regimen.. Ninety-one patients were diagnosed with breast cancer MC from 2000 to 2007. Intrathecal treatment was MTX 15 mg/day (days 1-5), hydrocortisone acetate (day 1) and oral folinic acid (days 1-5), repeated every 2 weeks. Patients and tumor characteristics were associated with the early clinical and biological outcome and with the overall survival (OS).. The median survival was 4.5 months (range 0-53). In multivariate analysis, adverse prognostic factors at diagnosis were performance status >2 [P = 0.006, response rate (RR) = 0.33 (0.15-0.71)], more than three chemotherapy regimens before MC diagnosis [P = 0.03, RR = 0.40 (0.19-0.93)], negative hormone receptor status [P = 0.02, RR = 0.4 (0.19-0.90)] and high Cyfra 21-1 level [P = 0.048, RR = (0.09-0.99)]. Clinical progression after one cycle and biological response after two cycles were independently associated with OS [P < 0.001, RR = 0.09 (0.02-0.37) and P = 0.003, RR = 3.6 (1.5-8.5), respectively]. We propose a prognostic score in order to define three distinct groups of prognosis.. MC presents a poor prognosis, but 1-year survival rate was 25%. This score may become a useful tool for treatment decision and clinical trials.

Topics: Adult; Aged; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Leucovorin; Meningeal Carcinomatosis; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Survival Rate; Vitamin B Complex

Edotecarin (J-107088), a novel inhibitor of topoisomerase I has an additive effect on colon cell lines (HCT-116) when combined with 5-fluorouracil (5-FU). We conducted a phase I study to determine the maximum tolerated dose and recommended a phase II dose of edotecarin in combination with infusional 5-FU/leucovorin (LV) in patients with advanced solid tumors. Patients and cohorts of three to six patients were sequentially enrolled at progressively higher dose levels of edotecarin administered as a 1-h intravenous (IV) infusion every 2 weeks. The edotecarin starting dose was 6 mg/m, followed by 200 mg/m LV IV infusion administered over 2 h, then 400 mg/m bolus dose of 5-FU before the start of 2400 mg/m 5-FU continuous infusion for a further 46 h. Patients were evaluated for safety, pharmacokinetics, and tumor response according to the Response Evaluation Criteria in Solid Tumors criteria. Fourteen patients (10 male; four female) received a total of 90 cycles (range 3-18). Dose-limiting toxicities were observed in five of the 14 patients treated in the study. All dose-limiting toxicities were related to neutropenia. Only the 6 and 8 mg/m edotecarin dose levels were explored; however, no maximum tolerated dose was declared. One confirmed complete response in a patient with hepatocellular carcinoma and seven stable disease responses were achieved in the 14 treated patients. Pharmacokinetic analysis showed that edotecarin achieved and maintained apparent steady-state plasma concentrations during the IV administration in both the cycles. The administration of edotecarin in combination with infusional 5-FU/LV once every 14 days, even without the 5-FU bolus, did not permit adequate time for recovery from neutropenia.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Topoisomerase I Inhibitors

To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC).. Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117).. No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56% vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated.. This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome

The present study evaluated the efficacy and safety of oxaliplatin, UFT, and leucovorin in metastatic gastric cancer.. Patients received intravenous oxaliplatin 130 mg/m(2) on day 1, followed by oral UFT capsules (350 mg/m(2) per day) and leucovorin tablets (90 mg/day), every 8 h, for 14 days, in a 3-week cycle.. Twenty-three patients (61% with > or = 2 metastatic sites), median age of 60 years (range, 39-69 years) were entered. Based on intention-to-treat analysis, one complete response and seven partial responses were found, resulting in an overall response rate (RR) of 35% (95% confidence interval [CI], 16-54), a median time to progression of 4 months (95% CI, 0.5-7.5), and a median overall survival (OS) of 8 months (95% CI, 4.5-11.5). The 1-year survival rate was 26%. Three patients did not complete the first course of 2 weeks; 1 died suddenly on day 16 with fatal lung embolism; 1 had rapid progressive disease and 1 experienced gastric hemorrhage on day 15 - both these patients withdrew. In the 20 patients assessable for toxicity no grade 4 toxicity occurred, grade 3 toxicity consisted of anemia in 1, diarrhea in 2, and neurotoxicity in 3 patients. No hand-foot syndrome (HFS) occurred.. Oxaliplatin is an effective drug in gastric cancer, but, as previously reported, its feasibility in combination with capecitabine is hampered due to combined hand-foot-based toxicity. The present phase II study of a combination of oxaliplatin with UFT and leucovorin appears to have efficacy and tolerability comparable to two other drug regimens used in gastric cancer, without the HFS problem.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Stomach Neoplasms; Survival; Tegafur; Treatment Outcome; Uracil

As a project of the Kanagawa Colorectal Cancer Study Group, we performed this study to analyze the efficacy and the safety of modified FOLFIRI (irinotecan: 150 mg/m2) therapy for Japanese patients with metastatic colorectal cancer.. We treated PS 0-1 Japanese patients with measurable or assessable colorectal cancer who either had not received preliminary treatment, or were postoperative with metastasis and had undergone radiation therapy or adjuvant chemotherapy before more than four weeks, and further had provided written acceptance of our proposed procedures. Twenty patients received modified FOLFIRI therapy as a 2-hour infusion of CPT-11 150 mg/m/2 and l-LV 200 mg/m2 followed by a bolus 5-FU 400 mg/m/2 and 46-hour infusion 5-FU 2, 400 mg/m2. Tumor response was assessed by RECIST and toxicity by NCI-CTC.. Thirty males and seven females underwent an average 10 courses of treatment. This therapy achieved a 50% response rate, 80%disease-control rate, and 316+/-40 days PHS. Regarding hematological toxicity, 11 patients (55%) experienced leukemia, which developed to grade 3/4 in 5 (25%) of them. Twelve patients (65%) experienced neutropenia, which developed to grade 3/4 in 10 (50%) of them. Digestive toxicity was observed in 16 patients (80%), which developed to grade 3/4 in only one patient (5%) with gastric ulcer. Six patients (30%) experienced alopecia, which was grade 1/2 only.. This clinical study was safely carried out. The efficacy was as good as in previous reports using a regular dose of CPT-11.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Asian People; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Rate

Docetaxel plus cisplatin and 5-fluorouracil has become a new standard for treating advanced gastric cancer. However, high rates of severe neutropenia limit its application. Modification of the regimen could be the solution to get similar activity but less myelosuppression.. Patients with histologically confirmed, locally advanced, or recurrent/metastatic gastric adenocarcinoma without previous chemotherapy were enrolled. This regimen consisted of docetaxel (Tyxan, TTY, Taipei, Taiwan) 30-min infusion at a dose of 36 mg m(-2), followed by cisplatin 30 mg m(-2) infusion over 1 h on days 1 and 8, and oral tegafur/uracil 300 mg m(-2) per day plus leucovorin 90 mg per day on days 1-14, every 3 weeks. Tumour response was evaluated after every 2 cycles of treatment.. From August 2007 to March 2009, 45 patients were enrolled. The median age was 56 years (range: 22-75). Among the 40 patients evaluable for tumour response, one achieved a complete response, 22 had partial responses and 11 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 58% (95% CI: 41-74%) and 53% (95% CI: 38-68%), respectively. The disease control rates in these populations were 85% (95% CI: 70-94%) and 82% (95% CI: 68-92%), respectively. In the ITT analysis, the median time to progression and overall survival were 6.8 and 13.9 months, respectively. Major grade 3-4 toxicities were neutropenia (51%), anaemia (22%), diarrhoea (16%), and infections (20%). No patient died of treatment-related toxicities.. Concurrent weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin are effective and well tolerated in the treatment of advanced gastric cancer.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Docetaxel; Drug Administration Schedule; Female; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Stomach Neoplasms; Taxoids; Tegafur; Uracil

Tetrathiomolybdate (TM) is an oral copper chelator under development as an anti-angiogenic agent. We evaluated TM in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL). Serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 6 (IL-6), and IL-8 were measured to evaluate the anti-angiogenic effect. Twenty-four patients with metastatic colorectal cancer were treated. The combination with IFL was well tolerated and dose intensity of IFL was maintained during combination therapy with TM. By intention to treat analysis, the overall response rate (RR) was 25% (95% CI 9.8-46.7) and the median time to progression (TTP) was 5.6 months (95% CI 2.7-7.7). VEGF levels were correlated with TTP, as were changes in VEGF, IL-8, and IL-6. TM can be safely added to IFL without compromising dose intensity or diminishing the expected RR. Changes in serum VEGF, IL-8, and IL-6 after treatment may directly reflect changes in CRC tissue angiogenesis.

Topics: Adenocarcinoma; Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chelating Agents; Colorectal Neoplasms; Copper; Cytokines; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Molybdenum; Neoplasm Metastasis; Pilot Projects

Irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI) is accepted as a reference treatment for the first-line treatment of patients with metastatic colorectal cancer (MCRC). The aim of this study was to demonstrate that a regimen without leucovorin (LV) (FUIRI) is not inferior to the standard FOLFIRI (response rate).. Chemotherapy-naive patients with MCRC were randomized to receive either irinotecan (180 mg/m(2) on day 1) + 5-fluorouracil (5-FU) (400 mg/m(2) bolus and 600 mg/m(2) 22-h infusion) + LV (200 mg/m(2) on days 1-2) (FOLFIRI) every 2 weeks or irinotecan (80 mg/m(2)) + 5-FU (2.250 mg/m(2) 48-h infusion) (FUIRI) weekly.. In all, 346 patients were included, 173 in each arm. In the intention-to-treat analysis, the response rates for FOLFIRI and FUIRI were 57% [95% confidence interval (CI) 49% to 64%] and 51% (95% CI 43% to 59%), respectively (P = 0.2809). No statistically significant differences were observed between FOLFIRI and FUIRI regarding median progression-free survival (8.3 versus 8.4 months; P = 0.4339) nor median overall survival (21.6 versus 19.2 months; log-rank test P = 0.2941). Grade 3/4 neutropenia was significantly more frequent on FOLFIRI arm (27% versus 9%), while the proportion of diarrhea was higher on FUIRI arm (21% versus 42%).. FUIRI represents a valid alternative without LV to the FOLFIRI regimen as MCRC first-line treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Proportional Hazards Models; Spain; Survival Analysis; Time Factors; Treatment Outcome

Oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (LV) are standard first-line treatments for patients with metastatic colorectal cancer (mCRC). The aim of this multicentre, open-label, phase IIIb study was to assess the addition of oxaliplatin to two different 5-FU regimens.. Patients with previously untreated mCRC were randomised to arm A [two-weekly oxaliplatin 85 mg/m(2) + either continuous intravenous infusion (CIV) of 5-FU without LV or two-weekly bolus and CIV 5-FU + LV (LV5FU2)] or arm B (5-FU CIV or LV5FU2 alone). Irinotecan monotherapy was planned on progression.. A total of 725 patients were enrolled. After a fixed follow-up of 2 years for each patient, 2-year survival rates were 27.3% and 24.8% in arms A and B, respectively (hazard ratio 0.93; 95% confidence interval 0.78-1.10). The addition of oxaliplatin significantly improved response rates (54.1 versus 29.8%; P < 0.0001) and median progression-free survival (7.9 versus 5.9 months; P < 0.0001). The most common grade 3-4 toxic effects were neutropenia (arm A, 33%; arm B, 5%), diarrhoea (arm A, 14%; arm B, 8%), and fatigue (arm A, 9%; arm B, 8%).. Despite improved rates of tumour control, these results failed to demonstrate a survival benefit from the addition of oxaliplatin to infused 5-FU and lend further support to the use of sequential monotherapy in some patients with mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; Time Factors; Treatment Outcome

This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated.. Patients received cetuximab (400 mg/m(2) initial dose followed by 250 mg/m(2)/wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1, plus leucovorin 200 mg/m(2) and fluorouracil as a 400 mg/m(2) bolus followed by a 600 mg/m(2) infusion during 22 hours on days 1 and 2; n = 169) or FOLFOX-4 alone (n = 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n = 233).. The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio = 1.52; P = .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated.. KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Patient Compliance; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins

Simvastatin has demonstrated anti-tumor activity in preclinical studies via tumor cell senescence, anti-angiogenesis, and apoptosis. This phase II trial evaluated the efficacy and toxicity profile of conventional FOLFIRI chemotherapy plus simvastatin in metastatic colorectal cancer patients.. Patients received irinotecan 180 mg/m(2) as a 90-min infusion followed by leucovorin 200 mg/m(2) in a 2-h infusion, and then 5-FU 400 mg/m(2) bolus injection followed by 2,400 mg/m(2) as a 46-h continuous infusion. Treatment cycles were repeated every 2 weeks until documented disease progression, unacceptable toxicity, or patient's refusal. Simvastatin 40 mg tablet was given once daily per oral everyday during the period of chemotherapy without a rest.. From October 2005 to June 2006, 49 patients were enrolled. The overall response rate (ORR) was 46.9% (95% CI, 31.0-58.8) by intent-to-treat analysis and 45.8% (95% CI, 33.3-62.8) by per-protocol analysis. There were one complete response (CR) and 22 partial responses (PRs). Both CR and PRs were confirmed at least 4 weeks later. The disease-control rate was 83.7% (95% CI, 73.4-94.0). The median follow-up duration was 25.6 months (range, 20.9-28.8 months). The median survival of all patients was 21.8 months (95% CI, 14.4, 29.2). The median TTP was 9.9 months (95% CI, 6.4, 13.3). No patients experienced additional adverse effect that was definitely caused by simvastatin drug therapy in this trial.. The combination of simvastatin plus FOLFIRI was a feasible regimen with promising antitumor activity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Simvastatin

To evaluate the efficacy and safety profile of a triplet regimen consisting of gemcitabine, oxaliplatin, and infusional fluorouracil and leucovorin (LV) in advanced pancreatic carcinoma (APC).. Chemotherapy-naïve patients with histo-/cytologically proven unresectable APC, and bi-dimensionally measurable diseases were eligible. Treatment consisted of fixed-dose rate (10 mg/m(2)/min) infusion of 800 mg/m(2) gemcitabine followed by 2-h infusion of 85 mg/m(2) oxaliplatin and then 48-h infusion of fluorouracil and LV (3,000 and 300 mg/m(2), respectively) every 2 weeks (the GOFL regimen). The primary end-point was objective response rate.. Forty-five patients were enrolled and received a median of seven [95% confidence interval (CI) 6.4-8.8] cycles of treatment. On intent-to-treat analysis, the overall response and disease-control rates were 33.3% (95% CI 21.4-48.0%) and 68.9% (95% CI 54.8-83.0%), respectively. Clinical benefit response was observed in 46.2% of initially symptomatic patients. The median time-to-tumor progression and overall survival were 5.1 (95% CI 4.0-6.3) months and 8.7 (95% CI, 6.1-11.3) months, respectively. Major grade 3-4 toxicities were neutropenia (28.9%, with 4.4% complicated with fever), peripheral sensory neuropathy (15.6%), nausea/vomiting (13.3%), and diarrhea (6.7%).. The triplet regimen is feasible and exhibits promising activity against APC, deserving further exploration.

Topics: Adult; Aged; Antineoplastic Agents; Deoxycytidine; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Survival Rate; Treatment Outcome

We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab.. We randomly assigned patients with epidermal growth factor receptor-positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival.. A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab-FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P=0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P=0.31). There was a significant interaction between treatment group and KRAS mutation status for tumor response (P=0.03) but not for progression-free survival (P=0.07) or overall survival (P=0.44). The hazard ratio for progression-free survival among patients with wild-type-KRAS tumors was 0.68 (95% CI, 0.50 to 0.94), in favor of the cetuximab-FOLFIRI group. The following grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone: skin reactions (which were grade 3 only) (in 19.7% vs. 0.2% of patients, P<0.001), infusion-related reactions (in 2.5% vs. 0%, P<0.001), and diarrhea (in 15.7% vs. 10.5%, P=0.008).. First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. (ClinicalTrials.gov number, NCT00154102.)

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease Progression; ErbB Receptors; Female; Fluorouracil; Genes, ras; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Young Adult

This study was designed to investigate the efficacy and safety of the epidermal growth factor receptor (EGFR) inhibitor cetuximab combined with irinotecan, folinic acid (FA) and two different doses of infusional 5-fluorouracil (5-FU) in the first-line treatment of EGFR-detectable metastatic colorectal cancer.. The 5-FU dose was selected on the basis of dose-limiting toxicities (DLTs) during part I of the study. Patients received cetuximab (400 mg/m2 initial dose and 250 mg/m2/week thereafter) and every 2 weeks irinotecan (180 mg/m2), FA (400 mg/m2) and 5-FU (either low dose [LD], 300 mg/m2 bolus plus 2,000 mg/m2 46-hour infusion, n = 7; or, high-dose [HD], 400 mg/m2 bolus plus 2,400 mg/m2; n = 45).. Only two DLTs occurred in the HD group, and HD 5-FU was selected for use in part II. Apart from rash, commonly observed grade 3/4 adverse events such as leucopenia, diarrhoea, vomiting and asthenia occurred within the expected range for FOLFIRI. Among 52 patients, the overall response rate was 48%. Median progression-free survival (PFS) was 8.6 months (counting all reported progressions) and the median overall survival was 22.4 months. Treatment facilitated the resection of initially unresectable metastases in fourteen patients (27%): of these, 10 patients (71%) had no residual tumour after surgery, and these resections hindered the estimation of PFS.. The combination of cetuximab and FOLFIRI was active and well tolerated in this setting. Initially unresectable metastases became resectable in one-quarter of patients, with a high number of complete resections, and these promising results formed the basis for the investigation of FOLFIRI with and without cetuximab in the phase III CRYSTAL trial.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Diarrhea; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Exanthema; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Leukopenia; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Treatment Outcome; Vomiting

Irinotecan-based chemotherapy regimens are 1 option for treatment of metastatic colorectal cancer (mCRC). The authors report the safety and efficacy of such regimens in elderly patients using a large phase III trial (bolus, infusional, or capecitabine with camptostar-celecoxib [BICC-C]) cohort.. In period 1, 430 previously untreated patients with mCRC were randomized in a 3-by-2 design to receive irinotecan plus infusional 5-fluorouracil, and leucovorin (FOLFIRI), irinotecan plus bolus 5-fluorouracil/leucovorin (mIFL), and irinotecan plus oral capecitabine (CapeIRI). In period 2, an additional 117 patients were randomized to receive FOLFIRI or mIFL and bevacizumab. In both periods patients were also randomized to a double-blind treatment with celecoxib or placebo. A secondary analysis was conducted examining the safety and efficacy of these regimens in elderly (age >70 years) versus nonelderly (age

Topics: Administration, Oral; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Celecoxib; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Pyrazoles; Sulfonamides; Survival Rate

Chemotherapy may improve survival in patients undergoing resection of colorectal liver metastases (CLM). Neoadjuvant chemotherapy may help identify patients with occult extrahepatic disease (averting unnecessary metastasectomy), and it provides in vivo chemosensitivity data.. A phase II trial was initiated in which patients with resectable CLM received CPT-11, 5-FU and LV for 12 weeks. Metastasectomy was performed unless extrahepatic disease appeared. Postoperatively, patients with stable or responsive disease received the same regimen for 12 weeks. Patients with progressive disease received either second-line chemotherapy or best supportive care. The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS) and safety.. 35 patients were accrued. During preoperative chemotherapy, 16 patients (46%) had grade 3/4 toxicities. Resection was not possible in 5 patients. One patient died of arrhythmia following surgery, and 1 patient had transient liver failure. During the postoperative treatment phase, 12 patients (55%) had grade 3/4 toxicities. Deep venous thrombosis (DVT) occurred in 11 patients (34%) at various times during treatment. Of those who underwent resection, median DFS was 23.0 mo. and median OS has not been reached. The overall survival from time of diagnosis of liver metastases was 51.6 mo for the entire cohort.. A short course of chemotherapy prior to hepatic metastasectomy may serve to select candidates best suited for resection and it may also direct postoperative systemic treatment. Given the significant incidence of DVT, alternative systemic neoadjuvant regimens should be investigated, particularly those that avoid the use of a central venous line.. ClinicalTrials.gov NCT00168155.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Treatment Outcome

Alkaline phosphatase (ALP) is a strong prognostic factor in patients with metastatic colorectal cancer (MCRC). Patients with ALP more than three times the upper limit of normal (ULN) were excluded from our previous studies evaluating chemotherapy. An exploratory cohort of patients with ALP >3 ULN was included in the OPTIMOX1 study.. Previously untreated patients with MCRC were randomized to FOLFOX4 until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). Patients were stratified according to ALP level

Topics: Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

The quality of life (QL) of advanced gastric cancer patients receiving irinotecan, folinic acid and 5-fluorouracil (5-FU) (IF arm) or cisplatin with 5-FU (CF arm) is presented.. Patients with measurable or evaluable advanced gastric cancer received IF weekly for 6/7 weeks or CF q4 weeks. QL was assessed using the EORTC QLQ-C30 at baseline, subsequently every 8 weeks until progression and thereafter every 3 months until death. The QL data were analysed using several statistical methods including summary measures and pattern-mixture modelling.. A total of 333 patients were randomised and treated (IF 170, CF 163). The time-to-progression for IF and CF was 5.0 and 4.2 months (P = 0.088), respectively. The overall compliance rates for QL questionnaire completion were 60 and 56% in the IF and CF arms, respectively. Significant treatment differences were observed for the physical functioning scale (P = 0.024), nausea\\vomiting (P = 0.001) and EQ-5D thermometer (P = 0.020) in favour of the IF treatment arm.. There was a trend in favour of IF over CF in time-to-progression. The IF group also demonstrated a better safety profile than CF and a better QL on a number of multi-item scales, suggesting that IF offers an alternative first-line platinum-free treatment option for advanced gastric cancer.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Esophagogastric Junction; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Neoplasm Metastasis; Palliative Care; Quality of Life; Stomach Neoplasms; Young Adult

To evaluate the efficacy of bevacizumab in combination of irinotecan,fluorouracil and leucovorin for metastatic colorectal cancer treated by failed prior oxaliplatin -based regiment.. Sixty-two patients were randomly divided into two groups, group A of 30 patients received bevacizumab plus irinotecan, fluorouracil and leucovorin, group B of 32 patients received irinotecan, fluorouracil and leucovorin. The response rate,change of tumor markers,one year survival rate and safety were observed.. Tumor response rate was 30% in group A, 21.8% in group B respectively. Disease control rate(CR+PR+SD) was 80% in group A, 50% in group B. The obvious change of concentration of tumor markers was observed between pre-treatment and post-treatment, which was significantly different in group A(P<0.05). One year survival rate, median of time to progression and median duration of survival between group A and group B were 26.7% vs 18.8%, 5.9 months vs 3.9 months, 10.9 months vs 8.9 months(P<0.05). The adverse effect in group A was the same as group B. Bevacizumab was associated with hypertension and bradycardia.. The chemotherapy of bevacizumab combined with irinotecan, fluorouracil and leucovorin results in better efficacy in patients with progressive metastatic colorectal cancer.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Survival Rate

Bevacizumab (Avastin) significantly improves overall survival (OS) and progression-free survival (PFS) when combined with first-line irinotecan (IFL) plus bolus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic colorectal cancer (CRC). This open-label, phase IV trial evaluated the efficacy and safety of first-line bevacizumab in combination with IFL and infusional 5-FU/LV (FOLFIRI).. Two-hundred and nine treatment-naïve metastatic CRC patients were enrolled and received bevacizumab and FOLFIRI every 2 weeks. Treatment was continued until disease progression. The primary objective was PFS, with additional determinations of OS, response and toxicity.. Median PFS was 11.1 months and is comparable to that observed in published phase III and community-based trials using first-line bevacizumab plus FOLFIRI, and to phase III trials using bevacizumab in combination with bolus 5-FU/LV plus IFL. Median OS was 22.2 months. Overall response rate was 53.1% and the disease control rate 85.6%. Most adverse events were grade 1/2 and were manageable. The most common grade 3/4 adverse events (> or =10%) were neutropenia, venous thromboembolic events, diarrhea, and fatigue.. Bevacizumab combined with first-line FOLFIRI is an effective and well-tolerated therapy option for patients with metastatic CRC.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Time Factors

We aimed to evaluate the safety and efficacy of combination chemotherapy with biweekly irinotecan (CPT-11) plus oral tegafur/uracil (UFT) and leucovorin (LV) in patients with previously untreated metastatic colorectal adenocarcinoma in phase I/II setting.. We recruited 37 patients with histologically proven metastatic colorectal adenocarcinoma. UFT (300 mg/m(2) per day) and LV (75 mg/day) were administered orally on days 1-21. CPT-11 was administered intravenously on day 1 and 15, at an initial dose of 60 mg/m(2), stepping up to 150 mg/m(2) in a traditional phase I fashion. The treatment was repeated every 4 weeks. After patients enrolled into a phase II portion, the efficacy and toxicity of this regimen were also assessed.. The recommended dose of CPT-11 was determined to be 150 mg/m(2). Although one patient had a pulmonary embolism after 60 mg/m(2) of CPT-11, the treatment was well tolerated in general. The overall objective response rate was 37.8% (14/37; 95% CI, 22.5-55.2) in all patients. Median progression-free survival was 226 days (95% CI, 133-276).. Biweekly CPT-11 plus UFT and LV had a reasonable safety profile with manageable toxicity, and had a promising activity in patients with metastatic colorectal cancer. Further trials are indicated based on the promising results observed in this study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Humans; Irinotecan; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Tegafur; Uracil

This study was designed to determine the efficacy and safety of biweekly oxaliplatin in combination with infusional 5-fluouracil (5-FU) and leucovorin in patients with advanced gastric cancer (AGC). Fifty-five eligible patients with measurable or assessable M/AGC (median age 62 and 90% of patients presented with metastasis) received oxaliplatin (85 mg/m2) intravenous infusion for 2 h, followed by intravenous infusion of 5-FU (3000 mg/m2) and leucovorin (100 mg/m2) for 46 h every 14 days until the patient's disease was either in progression, unacceptable toxicity, patient's withdrawal or the investigators' decision to discontinue treatment. Of the 55 enrolled patients, 48 were evaluable for response. Three patients (5.4%) showed complete remission and 20 patients (36.4%) achieved partial response. The overall response rate was 47.9%. Nineteen patients (34.5%) had stable disease and six patients (10.9%) showed progressive disease. The median time to progression was 5.6 months and the median overall survival was 10.8 months. Grade 3/4 toxicities included leucopenia (12.7%), thrombocytopenia (5.4%), diarrhoea (3.6%) and vomiting (9.1%). Peripheral neuropathy was noted in 61.8% of the patients (grade 1/2: 54.5%; grade 3: 7.3%). Our study confirmed that the combination of oxaliplatin and continuous infusion of 5-FU/leucoverin without bolus 5-FU as first-line chemotherapy is active for patients with AGC and relatively safe with lower haematological toxicity.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Remission Induction; Stomach Neoplasms; Survival Rate; Taiwan; Treatment Outcome

Biliary tract carcinoma is often diagnosed at an advanced stage, and there is currently no established palliative standard of care. This phase II study investigated the efficacy and safety of combination chemotherapy of oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) in biliary tract carcinoma. Patients with unresectable or recurrent biliary tract carcinoma were enrolled, including pretreated and chemotherapy-naive patients. Treatment consisted of intravenous oxaliplatin (100 mg/m2, day 1) followed by leucovorin (100 mg/m2, day 1) and 5-FU (1000 mg/m2, days 1 and 2). Treatment was repeated every 3 weeks. The efficacy and safety of the treatment were determined. Twenty-eight patients were evaluable, and a total of 166 cycles were administered (median five cycles). One complete response (3.6%) and five partial responses (17.9%) were noted, with a response rate of 21.5% [95% confidence interval (CI): 6.2-36.7], according to Response Evaluation Criteria in Solid Tumors criteria. The median time to progression and overall survival was 3.5 months (95% CI: 2.7-4.3) and 10.0 months (95% CI: 7.2-12.8), respectively. The 1-year survival rate was 17.8%. Grade 3/4 neutropenia and thrombocytopenia were recorded in 18 and 4% of the patients, respectively. No treatment-related death was observed. Oxaliplatin in combination with leucovorin and 5-FU should be considered a feasible chemotherapy regimen for patients with recurrent/metastatic biliary tract carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin

To demonstrate the noninferiority of capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX-4) as second-line therapy in patients with metastatic colorectal cancer after prior irinotecan-based chemotherapy.. A total of 627 patients were randomly assigned to receive XELOX (n = 313) or FOLFOX-4 (n = 314) following disease progression/recurrence or intolerance to irinotecan-based chemotherapy. The primary end point was progression-free survival (PFS).. PFS for XELOX was noninferior to FOLFOX-4 [hazard ratio (HR) = 0.97; 95% confidence interval (CI) 0.83-1.14] in the intention-to-treat (ITT) population. Median PFS was 4.7 months with XELOX versus 4.8 months with FOLFOX-4. The robustness of the primary analysis was supported by multivariate and subgroup analyses. Median overall survival in the ITT population was 11.9 months with XELOX versus 12.5 months with FOLFOX-4 (HR = 1.02; 95% CI 0.86-1.21). Treatment-related grade 3/4 adverse events occurred in 50% of XELOX- and 65% of FOLFOX-4-treated patients. Whereas grade 3/4 neutropenia (35% versus 5% with XELOX) and febrile neutropenia (4% versus < 1%) were more common with FOLFOX-4, grade 3/4 diarrhea (19% versus 5% with FOLFOX-4) and grade 3 hand-foot syndrome (4% versus < 1%) were more common with XELOX.. XELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

The combination of docetaxel (Taxotere), cisplatin, and fluorouracil improved efficacy in gastric cancer, but was associated with substantial toxicity. This study was designed to incorporate docetaxel into a tolerable biweekly (once every 2 weeks) oxaliplatin-based chemotherapy regimen.. Patients with measurable, metastatic adenocarcinoma of the stomach or esophagogastric junction and no prior chemotherapy received oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 2600 mg/m(2) as a 24-h infusion in combination with docetaxel 50 mg/m(2) (FLOT) on day 1 every 2 weeks. Prophylactic growth factors were not administered.. Fifty-nine patients were enrolled; 54 received treatment. Patients had a median age of 60 years (range 29-76) and most (93%) of them had metastatic disease. Objective responses were observed in 57.7% of patients with a median time to treatment response of 1.54 months. Median progression-free survival (PFS) and overall survival were 5.2 and 11.1 months, respectively. Twenty-five percent of patients experienced prolonged (>12 months) PFS. Frequent (>10%) grade 3 or 4 toxic effects included neutropenia in 26 (48.1%), leukopenia in 15 (27.8%), diarrhea in 8 (14.8%), and fatigue in 6 (11.1%) patients. Complicated neutropenia was observed in two (3.8%) patients, only.. Biweekly FLOT is active and has a favorable safety profile.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Esophageal Neoplasms; Esophagogastric Junction; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Stomach Neoplasms; Taxoids

The combination of vaccines and chemotherapy holds promise for cancer therapy, but the effect of cytotoxic chemotherapy on vaccine-induced antitumor immunity is unknown. This study was conducted to assess the effects of systemic chemotherapy on ALVAC-CEA/B7.1-induced T-cell immunity in patients with metastatic colorectal cancer.. Patients with metastatic colorectal cancer were treated with fluorouracil, leucovorin, and irinotecan and were also given ALVAC-CEA/B7.1 vaccine with or without tetanus toxoid adjuvant. Eligible patients were randomized to ALVAC followed by chemotherapy and booster vaccination (group 1), ALVAC and tetanus toxoid followed by chemotherapy (group 2), or chemotherapy alone followed by ALVAC in patients without disease progression (group 3). Humoral immune responses were measured by standard ELISA assay, and carcinoembryonic antigen (CEA)-specific T-cell responses were measured by IFN-gamma enzyme-linked immunospot assay.. One hundred eighteen patients were randomized to receive either ALVAC before and concomitantly with chemotherapy (n = 39), ALVAC with tetanus adjuvant before and concomitantly with chemotherapy (n = 40), or chemotherapy followed by ALVAC (n = 39). Serious adverse events were largely gastrointestinal (n = 30) and hematologic (n = 24). Overall, 42 patients (40.4%) showed objective clinical responses. All patients developed antibody responses against ALVAC, but increased anti-CEA antibody titers were detected in only three patients. Increases in CEA-specific T cells were detected in 50%, 37%, and 30% of patients in groups 1, 2, and 3, respectively. There were no differences in clinical or immune responses between the treatment groups.. The combination of ALVAC-CEA/B7.1 vaccine and systemic chemotherapy has an acceptable safety profile in patients with metastatic colorectal cancer. Systemic chemotherapy did not affect the generation of CEA-specific T-cell responses following vaccination.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; B7-1 Antigen; Camptothecin; Carcinoembryonic Antigen; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; T-Lymphocytes; Treatment Outcome; Viral Vaccines

Prolonged infusions have been shown to be safer and potentially more effective than bolus regimens of 5-fluorouracil (5-FU) as treatment for metastatic colorectal cancer (mCRC). However, infusional 5-FU requires central venous access and costly infusion pumps. Oral fluoropyrimidines enable longer exposures to 5-FU with increased convenience. Tegafur-uracil (UFT) with leucovorin (LV) given thrice daily has improved safety plus comparable survival and response rates to bolus 5-FU/LV. We conducted a phase II clinical study in 98 patients with mCRC to evaluate if UFT with LV given twice daily provided comparable time to progression (TTP), efficacy and tolerability to that reported for thrice daily in two phase III clinical studies. Secondary objectives included overall response rate (ORR) and overall survival (OS). Median TTP was 3.8 months, when compared with 3.5 months for thrice daily. The ORR (11%) and median OS (12.8 months) with twice daily administration were similar to that of thrice daily administration (12% and 12.4 months). The incidence of grade 3/4 treatment-related diarrhoea was 30% on the twice daily and 21% on the thrice daily schedule. These results suggest that twice daily administration has similar efficacy and tolerability to thrice daily administration and is an acceptable alternative for patients who would benefit from UFT with LV therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Tegafur; Treatment Outcome; Uracil

Irinotecan (CPT-11), a specific inhibitor of topoisomerase I, has been proven to be effective in the treatment of refractory or metastatic colorectal cancer. Furthermore, several first line phase III trials of the combination therapy (FOLFIRI) using CPT-11 and fuorouracil/leucovorin (5-Fu/LV) were reported to have significant improvement in treatment result. Therefore, we designed a multicenter clinical study to observe the overall survival (OS), time to death (TTD), time to progression (TTP), efficacy and safety of FOLFIRI regimen for patients with refractory or metastatic colorectal cancer after first line chemotherapy failure.. Patients with metastatic or refractory colorectal cancer after first line oxaliplatin-based chemotherapy failure were enrolled into this prospective, one arm and open-labeled multicenter study. Irinotecan 180 mg/m2 was administered biweekly on D1, LV 200 mg/m2 by intravenous infusion in 2 hours before bolus intravenous injection of 5-Fu 400 mg/m2, then followed immediately by intravenous infusion of 5-Fu 2.4 g/m2 in 46 hours. OS, TTD, TTP, response rate (RR) and adverse events were assessed according to RSCIST criteria and NCIC-CTG CTCAE (3.0).. Sixty-six patients were valuable for safety assessment and and 61 for efficacy. There was no CR patient in this series. Ten patients had PR, 35 SD (57.4% ) and 16 PD (26.2%) with a response rate of 16.4% (10/61). The median TTP was 5.0 months (1-12 months), median TTD 9.9 months (5-27 months)and median OS 18.2 months (7-33 months). The adverse events including nausea,vomiting, anorexia,diarrhea, leucopenia and cholinergic syndrome were frequent, but usually in I - II degree. The rate of III/IV degree diarrhea and leucopenia was 7.6% and 22.7%, respectively.. The regimen of irinotecan plus fuorouracil/leucovorin (FOLFIRI) is effective and well-tolerated as a second-line chemotherapy and may prolong the overall survival for the patient with refractory or metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Disease Progression; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neutropenia; Prospective Studies; Rectal Neoplasms; Remission Induction; Survival Rate; Vomiting; Young Adult

To compare the time to deterioration in health-related quality of life (HRQoL) in patients with previously untreated metastatic colorectal cancer receiving a 5-fluorouracil (5-FU)-based chemotherapy regimen with or without the addition of bevacizumab (BV) in two randomized, placebo-controlled studies.. Prespecified HRQoL endpoints in the phase II (Study 2192) and phase III (Study 2107) studies were time to deterioration in HRQoL, measured by the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) Colorectal Cancer Subscale (CCS), Trial Outcome Index (TOI-C), and FACT-C total score. Time to deterioration in HRQoL was evaluated for patients with baseline and postbaseline assessments, using the stratified log-rank test.. In the pivotal phase III trial, HRQoL baseline and postbaseline CCS scores were available for 127 patients receiving irinotecan, 5-FU, and leucovorin (LV) (IFL) and 122 patients receiving IFL plus BV. The time to deterioration in HRQoL did not differ significantly between treatment groups as measured by the CCS, TOI-C, or FACT-C total score. In the phase II study, baseline and postbaseline CCS scores were available for 77 and 89 patients receiving 5-FU and LV and 5-FU and LV plus BV, respectively. In that study, the time to deterioration in HRQoL was similar between groups as measured by the CCS and TOI-C scores, but was significantly longer in the 5-FU and LV plus BV arm than in the 5-FU and LV plus placebo arm for the FACT-C total score.. When added to 5-FU chemotherapy, BV significantly prolonged overall survival and progression-free survival without compromising HRQoL.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Prospective Studies; Quality of Life; Treatment Outcome

A combination of CPT-11, continuous 5-fluorouracil(5-FU)and leucovorin(LV), the Arbeitsgemeinschaft für Internistische Onkologie(AIO)regimen, is widely used for the treatment of metastatic CRC. The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC. Our objective was to evaluate the safety of the AIO regimen plus CPT-11 in Japanese colorectal carcinoma(CRC)patients. We investigated the maximum tolerated dose(MTD), dose-limiting toxicity(DLT), and recommended dose(RD)for CPT-11 and continuous 5-FU. CPT-11, 5-FU, and l-LV were administered on days 1, 8, and 15 of a 28-day cycle. The dose of CPT- 11 was escalated from 40 mg/m2 (level 1)to 80 mg/m2 (level 3). The 5-FU dose was then escalated from 1,000 mg/m2 (level 4)to 2,000 mg/m2 (level 5). If neither level met the criteria for the MTD, the recommended dose was defined as level 5, and the dose escalation was discontinued, because the maximum approved weekly dose of CPT-11 alone in Japan is 80 mg/m2 and the dose of 5-FU in the original AIO regimen was 2,000 mg/m2. A total of 18 patients were enrolled in this study. Hematological and non-hematological toxicity were infrequent and mild. There were no toxicities greater than grade 2 at each dose level. Level 5 did not meet the MTD criteria. Our results confirm that the modified AIO plus CPT-11 regimen is safe for Japanese patients. The recommended doses in the present study were CPT-11 80 mg/m2, 5-FU 2,000 mg/m2, and l-LV 250 mg/m2.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Tomography, X-Ray Computed

We investigated the gefitinib, 5-fluorouracil (5-FU), leucovorin and oxaliplatin (IFOX) regimen as first-line therapy in patients with metastatic colorectal cancer.. Eligible patients had stage IV colorectal adenocarcinoma, and had not received prior chemotherapy for metastatic disease. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin, leucovorin, and 5-FU (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg orally daily throughout the 14-day cycle.. Forty-five patients were enrolled and were assessable for toxicity. Forty-three patients were assessable for response. Thirty-one of the 43 patients (72%) had either a complete or partial response by the Response Evaluation Criteria in Solid Tumors. Median overall survival was 20.5 months. Median time to progression was 9.3 months. Commonly encountered grade 3 or 4 toxicities included diarrhea in 67% of patients and neutropenia in 60%. Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients.. IFOX is an active first-line regimen in patients with metastatic colorectal adenocarcinoma, showing higher response rates but also increased toxicities compared with FOLFOX-4 alone in a similar patient population.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Gefitinib; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Quinazolines

ATP-binding cassette, sub-family C, number 2 (ABCC2) is involved in the biliary excretion of irinotecan and its metabolites, SN-38 and SN-38 glucuronide. Effects of the ABCC2 genotype on the pharmacokinetics (PK) of irinotecan and the metabolites were examined in Japanese patients with metastatic colorectal cancer receiving irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI). ABCC2 genotypes (-1549G>A, -1023G>A, -1019A>G, -24C>T, 1249G>A and 3972C>T) and haplotypes were analyzed for 67 patients with cancer. PK was also examined in a subset of 31 patients receiving FOLFIRI. Relationship between the ABCC2 genotypes or diplotypes and area under the time-concentration curve (AUC) of irinotecan and the metabolites normalized by irinotecan dose was analyzed. The lower AUC of irinotecan was seen in patients with A/A or G/A genotypes at 1249 of the ABCC2 gene than others (p=0.011, Mann-Whitney U teat). AUC of SN-38 in patients with A/A or G/A genotypes at -1023 was significantly lower than that in others (p=0.018). The haplotype I included -1023A (GAACGC) was the most frequent one with the allele frequency of 0.366. The AUC of SN-38 observed in patients with diplotypes harboring at least one haplotype I was lower than that observed in others (p=0.023). The haplotype IV consisted of 1249 (GGACAC) and was the fourth most frequent one with the allele frequency of 0.127. Patients with diplotypes carrying at least one haplotype IV showed lower AUC of irinotecan than others (p=0.011). Thus, ABCC2 genotype is one of the predictors of the variability of irinotecan PK in Japanese patients with metastatic colorectal cancer receiving FOLFIRI.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Genotype; Haplotypes; Humans; Inactivation, Metabolic; Infusions, Intravenous; Irinotecan; Japan; Leucovorin; Linkage Disequilibrium; Male; Middle Aged; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Metastasis; Polymorphism, Single Nucleotide

The aim of this study was to investigate the efficacy and safety of the combination chemotherapy of paclitaxel, infusional 5-fluorouracil (5-FU) and leucovorin (FLT regimen) in advanced gastric cancer. The primary end point was the time to progression (TTP).. Patients with evaluable disease with or without measurable lesions received 175 mg/m2 paclitaxel on day 1 followed by 20 mg/m2 leucovorin and 24-h infusion of 5-FU 1,000 mg/m2 (day 1-3) repeated every 3 weeks.. Sixty patients were enrolled. The median TTP and overall survival duration were 13 and 60 weeks, respectively. One-year survival rate was 53.3%. Of the 50 patients with measurable lesion, the overall response rate was 31.7%. The most common grade 3-4 adverse event was neutropenia (61.7%).. The FLT regimen showed an efficacy comparable to other regimens of cisplatin or anthracycline combinations with the advantage of remarkably low non-hematological toxicity. These data about the efficacy of this regimen need confirmation in a phase III trial.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Paclitaxel; Prognosis; Stomach Neoplasms; Survival Analysis

We evaluated the outcome of 140 patients aged > or = 70 years of age who received first-line treatment for metastatic colorectal cancer within the German phase III trial of FUFOX (5-fluorouracil/leucovorin/oxaliplatin) versus CAPOX (capecitabine/oxaliplatin).. One hundred forty (30%) elderly patients of 476 total patients were identified, and 138 patients received the CAPOX or FUFOX treatment.. Overall, treatment was well tolerated, and grade 3/4 toxicities were similar in both groups, with more gastrointestinal side effects in the elderly group but less neurosensory side effects. The response rate (RR) was comparable between both cohorts (49% in elderly patients vs. 52% in patients aged < 70 years). Median progression-free survival (PFS) was 7.7 months for patients aged > or = 70 years and 7.5 months for patients aged < 70 years (hazard ratio [HR], 1.07; 95% CI, 0.86-1.34). With regard to the chemotherapy regimen, there was no inferiority between FUFOX and CAPOX in patients aged > or = 70 years (7.9 months vs. 7.6 months). The median overall survival (OS) between FUFOX and CAPOX was comparable in patients aged > or = 70 years (14.4 months vs. 14.2 months). However, when compared with patients aged < 70 years, the median OS was significantly shorter (18.8 months vs. 14.4 months; P = 0.013; HR, 1.37; 95% CI, 1.07-1.76). This was consistent with our multivariate analysis, which revealed that age > or = 70 years was a negative factor for OS.. Oxaliplatin combined with 5-FU/leucovorin or capecitabine was generally well tolerated in elderly patients. Elderly patients had similar PFS and overall RRs compared with the population aged < 70 years, but the OS was shorter.

Topics: Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate

To evaluate whether capecitabine plus oxaliplatin (XELOX) is noninferior to fluorouracil. folinic acid, and oxaliplatin (FOLFOX-4) as first-line therapy in metastatic colorectal cancer (MCRC).. The initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX versus FOLFOX-4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 x 2 factorial design randomly assigned patients to XELOX versus FOLFOX-4, and then to also receive either bevacizumab or placebo. We report here the results of the analysis of the XELOX versus FOLFOX-4 arms. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecified primary end point for the noninferiority analysis was progression-free survival.. The intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1,400 patients after the start of the amended 2 x 2 design, for a total of 2,034 patients. The median PFS was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4-containing arms (hazard ratio [HR], 1.04; 97.5% CI, 0.93 to 1.16). The median overall survival was 19.8 months with XELOX versus 19.6 months with FOLFOX-4 (HR, 0.99; 97.5% CI, 0.88 to 1.12). FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX-4.. XELOX is noninferior to FOLFOX-4 as a first-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate

To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC).. Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS).. A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials.. The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Placebos

A recent study identified a prognostic model for survival in metastatic colorectal cancer patients which included WBC count, alkaline phosphatase (AP), number of metastatic sites, and patients' self-reported social functioning. The aim of this research is to validate this model on data from an independent sample.. This validation study is based on a prospective randomized controlled trial in patients with metastatic colorectal cancer conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Chronotherapy Group. Overall, 564 patients in 10 countries were enrolled. For the purpose of this independent validation, patients with health-related quality of life (HRQOL) baseline data were analyzed. HRQOL was assessed using the EORTC Quality of Life Questionnaire C30 (QLQ-C30). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival.. The previous model with an additional adjustment, by stratification for sex, was replicated and its parameters were confirmed to independently predict survival: WBC count with an hazard ratio (HR) of 1.31 (95% CI, 1.021 to 1.698; P = .034); AP with an HR of 1.53 (95% CI, 1.188 to 1.979; P = .001); number of sites involved with an HR of 1.90 (95% CI, 1.531 to 2.364; P < .0001); and patients' self-reported social functioning with an HR of 0.94 (95% CI, 0.905 to 0.976; P = .001). The latter translates into a 6% increase in the likelihood of an earlier death for every 10-point decrease in the social functioning scale of the EORTC QLQ-C30.. This study provides confirmatory evidence of the independent prognostic value of patients' self-reported social functioning in patients with advanced colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Patient Participation; Prognosis; Proportional Hazards Models; Prospective Studies; Quality of Life; Reproducibility of Results; Self-Assessment

A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, and survival.. Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m(2) FU plus 200 mg/m(2) folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg x h x L(-1)) previously established in other studies was reached.. An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m(2)/wk in arm A and 1,790 +/- 386 mg/m(2)/wk (range, 900 to 3,300 mg/m(2)/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003).. Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Body Surface Area; Colorectal Neoplasms; Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Female; Fluorouracil; France; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Models, Biological; Neoplasm Metastasis; Proportional Hazards Models; Prospective Studies; Time Factors; Treatment Outcome; Vitamin B Complex

Metronomic chemotherapy, at a minimally toxic dose and with a frequent schedule, is a potentially novel approach to the control of advanced cancer disease via a different mechanism from maximum tolerable doses chemotherapy. Taking advantage of the potential effectiveness of metronomic therapy, tegafur/uracil (UFT) was incorporated into an oxaliplation/infusioanl fluouracil (5-FU)/leucovorin (LV) protocol in this study. The primary endpoints were response rate, time to progression (TTP) and safety profile in 5-FU-pretreated metastatic colorectal cancers (CRCs).. Twenty-eight patients with metastatic CRCs resistant or refractory to 5-FU/LV were enrolled. Chemotherapy was administrated every 2 weeks sequentially with 2-h infusion of oxaliplatin (85 mg/m2) and LV (200 mg/m2), intravenous bolus 5-FU (400 mg/m2), 22-h infusion of 5-FU (600 mg/m2) on day 1 and then followed by 10-day daily oral UFT (200 mg/m2)/LV (30 mg/m2).. Partial response was seen in ten (35.7%) patients. The median TTP was 5.2 (95% CI: 4.16-6.31) months and the median overall survival was 13.4 (95% CI: 6.39-20.5) months. No grade 3 toxicities above 5% according to National Cancer Institute-Common Toxicity Criteria (NCI-CTC) occurred except sensory neuropathy (10.7%). No grade 4 toxicity, treatment-related mortality or hand-foot syndrome was found.. This study protocol with favorable toxicity profile is thus promisingly effective against 5-FU-pretreated metastatic CRCs. Given the present experience, an evaluation of the regimen as front-line treatment of metastatic CRC is planned.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Patient Selection; Survival Analysis; Tegafur; Uracil

Irinotecan at 180 mg/m2 combined with an infusional 5-fluorouracil/leucovorin (5-FU/LV) regimen (FOLFIRI) is a standard first line therapy for metastatic colorectal cancer (mCRC). This phase II study aimed to assess whether increasing the irinotecan dose in the first line FOLFIRI regimen would benefit mCRC patients.. Patients received FOLFIRI every 2 weeks for up to six cycles, comprising a 5-FU/LV regimen combined with irinotecan at 180 mg/m2 (cycle 1), increasing to 220 mg/m2 (cycle 2) and 260 mg/m2 (cycle 3 and subsequent cycles) dependent on toxicity. Efficacy and safety were determined in the intention to treat (ITT) population and in patients able to receive irinotecan at 260 mg/m2 for at least four cycles [high-dose (HD) population].. Fifty-four eligible patients were included. Among them, 44 (81.5%) formed the HD population. The ITT objective response rate was 48% (90%CI: 36-60) with 25/26 of the responses in the HD population. The disease control rate was 76% (90%CI: 65-85) and median overall survival was 20.4 months (90%CI: 6.4-27.1). The main grade 3/4 toxicities (ITT/HD populations) were neutropenia (61%/59%), and diarrhoea (18%/11%), respectively.. This study confirms the feasibility of increasing the standard dose of the irinotecan component of FOLFIRI to 260 mg/m2, for more than 80% of patients but does not support a clear advantage of this strategy on unselected mCRC patients.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer.. Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m(2) as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m(2) bolus i.v. and leucovorin 20 mg/m(2) i.v. on days 1 and 8 of a 21-day cycle. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m(2) and 5-FU to 500 mg/m(2).. Twenty-four patients received therapy. The starting doses proved to be the MTD, as attempts to increase the dose of either gefitinib or the chemotherapeutic agents resulted in dose-limiting toxicities. Gastrointestinal effects and bone marrow suppression were the principal toxicities; however, only 1/17 (6%) patients treated with the MTD had severe (grades 3-4) diarrhea and severe neutropenia occurred in only two (12%) patients. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. In ten patients treated with the MTD, the steady-state PK of gefitinib was not affected by IFL nor did gefitinib appear to influence the PK of either irinotecan or 5-FU.. Gefitinib can be safely combined with an intermittent weekly schedule of IFL. Evidence of promising activity should encourage further clinical evaluation of epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, combined with multiagent chemotherapy for metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Gefitinib; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Quinazolines

This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, irinotecan 240 mg m(-2) day 1; q21) or TEGAFOX (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, oxaliplatin 120 mg m(-2) day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3-4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1-55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6-51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12-23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Tegafur; Uracil

Development of treatments to improve the outcomes achieved with single-agent gemcitabine therapy for metastatic pancreatic cancer remains a research priority. G-FLIP (gemcitabine, 5-fluorouracil, leucovorin and cisplatin) is a four-drug regimen designed to maximize sequence-dependent synergy, while attempting to minimize toxicity among the four drugs. The dose-limiting toxicities and maximum tolerated dose of irinotecan as part of the G-FLIP regimen have been published. For phase II testing, G-FLIP consisted of sequential gemcitabine 500 mg/m2 at a fixed rate of 10 mg/m2/min, irinotecan 120 mg/m2, bolus 5-fluorouracil 400 mg/m2 and leucovorin 300 mg, followed by a 24-h 5-fluorouracil infusion of 1500 mg/m2 on day 1 and cisplatin 35 mg/m2 on day 2. Cycles were repeated every 14 days. Thirty-three patients with metastatic pancreatic cancer (22 men and 11 women) were treated and 31 were evaluable. Median patient age was 63 years (range 44-78 years) and median Karnofsky performance status score was 70-80. Estimated median time to disease progression was 171 days (6.1 months) and Kaplan-Meir-estimated median overall survival was 229 days (8.1 months). Twelve- and 18-month survivals were 33 and 21%, respectively. As per Response Evaluation Criteria in Solid Tumors criteria, 13 patients had stable disease, seven (22%) attained a partial response, and 10 (32%) had disease progression. One patient attained a complete response and two were not evaluable (one withdrew consent and one died suddenly, each after cycle 1). Treatment generally was well tolerated. Grade 3-4 toxicities/patient were thrombocytopenia (3.1%), leukopenia (15%), neutropenia (21%), neutropenic fever (3%), fatigue (18%) and thrombosis (12.5%). Common grade 1-2 toxicities per patient included nausea/vomiting (69%), diarrhea (45%), constipation (21%) and fatigue (39%). In conclusion, G-FLIP is a feasible outpatient regimen with acceptable toxicity for metastatic pancreatic cancer patients. Disease control rate (stable disease rate plus partial or complete responses) and 1-year survival outcomes are encouraging.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Cisplatin; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Advanced pancreatic carcinoma (APC) has a poor prognosis and chemotherapy remains the most common approach. Gemcitabine was the only drug recently approved for use as single agent therapy in APC. However, the combination of oxaliplatin and 5-fluorouracil (5-FU) has shown some promising results. This phase II trial was conducted to investigate the efficacy of oxaliplatin, 5-FU, and folinic acid (FOLFOX-6) in previously untreated APC patients.. We studied response rate, time to progression, and toxicity profile. Treatment included oxaliplatin 100 mg/m2 and folinic acid 400 mg/m2 on day 1 followed by a 5-FU bolus 400 mg/m2 and a 46-hour infusion of 3000 mg/m2 every 2 weeks.. From January 2003 through December 2004, 30 eligible patients were included. Median age was 65 (range, 38-75). There were 22 patients who had metastatic disease and 29 had an adenocarcinoma. A total of 181 cycles were delivered with a mean of 6 cycles per patient. There were 23 patients evaluable for response. There were 8 patients with partial response (27.6% response rate) and 10 with stable disease status (34.5%), while tumor growth control was found in 62% of the patients. Recorded toxicities of grade 3/4 were: neutropenia (26.67%), thrombocytopenia and anemia (10% each), diarrhea (6.67%), and mucositis (3.33%). Neurosensory toxicity was mild. The median time to progression and the median survival were 4 and 7.5 months, respectively.. In patients with APC, FOLFOX-6 regimen achieved an interesting response rate within a tolerable level of toxicity. This regimen seems to warrant further controlled investigation to confirm its efficacy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neuroendocrine Tumors; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Patient Selection

A phase II study was conducted to evaluate the toxicity and efficacy of irinotecan/5-fluorouracil/leucovorin (CPT-11/5-FU/LV (AIO schedule)) as salvage treatment in patients with metastatic colorectal cancer.. 33 patients relapsing after oxaliplatin (L-OHP)-based first-line chemotherapy were enrolled. Their median age was 69 years, 20 (61%) patients were male, and performance status (WHO) was 0, 1, and 2 in 15, 16 and 2 patients respectively; prior surgery 20 (61%) patients; adjuvant chemotherapy 11 (33%) patients, and adjuvant radiotherapy 6 (18%) patients. The number of metastatic sites was 1, 2, and > or =3 in 11, 11, and 11 patients, respectively. CPT-11 was administered on day 1 at the dose of 80 mg/m(2) in 30-90 min infusion and LV (500 mg/m(2)) on the same day as a 2-hour infusion followed by 5-FU (2,600 mg/m(2)/day) as a 22-hour infusion on day 1 for 6 subsequent weeks. The regimen was repeated every 7 weeks.. All patients were evaluable for toxicity and for response. Complete response was achieved in 2 patients (6%) and partial response in 4 patients (12%) (RR 18%, CI 5.95-35.43%); 13 patients (40%) had stable disease, and 14 (42%) progressive disease. After a median follow-up period of 9 months, the median duration of response was 5 months, the median time to progression 7.5 months, and OS 14 months. Grade 3-4 neutropenia occurred in 13 patients (39%), febrile neutropenia in 3 (9%), grade 2 anemia in 11 (33%), grade 4 thrombocytopenia in 1 (3%). Grade 3-4 diarrhea occurred in 12 patients (36%), grade 3-4 neurotoxicity in 3 (9%), and grade 3 asthenia in 4 (12%). No treatment-related deaths occurred. The median dose intensity was 85% for CPT-11, and 88% for 5-FU and LV.. The combination of weekly CPT-11 and infusional 5-FU/LV is an active and relatively well-tolerated regimen as salvage treatment in MCC.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Health Status; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Patient Compliance; Quality of Life; Salvage Therapy; Surveys and Questionnaires; Treatment Outcome

We conducted a randomised phase II study to compare irinotecan monotherapy with irinotecan in combination with infusional 5-fluorouracil/folinic acid (5-FU/FA) regarding efficacy and safety of these regimens in second-line therapy after failed fluoropyrimidine therapy in patients with metastatic colorectal cancer (mCRC).. 55 patients with mCRC after failure of a first-line therapy were randomised to receive either irinotecan 80 mg/m2 followed by FA 500 mg/m2 and 5-FU 2,000 mg/m2 24 h weekly for 6 weeks, with courses repeated on day 50 (arm A), or irinotecan 125 mg/m2 weekly for 4 weeks, with cycles repeated on day 43 (Arm B).. Both regimens yielded a partial response rate of 11% with identical progression-free survival (3.7 months for both regimens) and similar overall survival (9.5 months for the combination therapy vs. 10.7 months for the monotherapy). Both regimens were very well tolerated, and the combination of irinotecan with 5-FU/FA did not result in increased toxicity.. Our study confirms that irinotecan alone or in combination with infusional 5-FU/FA is an effective and safe regimen for CRC patients who failed first-line therapies. However, the role of 5-FU in addition to irinotecan for fluoropyrimidine failures remains unclear. Due to the small sample size, a decision cannot be made which therapy should be preferred, and a significant contribution to the efficacy of single-agent irinotecan is not obvious from this small randomised phase II trial.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Retreatment; Sample Size; Survival Rate; Treatment Failure

The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI).. Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR).. A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032).. The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Quality of Life; Recurrence; Survival Analysis

Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor and is indicated for patients with metastatic colorectal cancer (mCRC) who have experienced disease progression after standard chemotherapy. We conducted this phase II study to assess the ability of panitumumab to be administered with first-line irinotecan-containing regimens in patients with mCRC.. This was a 2-part multicenter study of panitumumab 2.5 mg/kg weekly with irinotecan, 5-fluorouracil (5-FU), and leucovorin. Part 1 used bolus 5-FU (IFL), and part 2 used infusional 5-FU (FOLFIRI). Tolerability (measured by grade 3/4 diarrhea) was the primary endpoint. Objective response, progression-free survival, overall survival, and safety were also examined.. Nineteen patients in part 1 and 24 patients in part 2 received panitumumab plus chemotherapy. Grade 3/4 diarrhea occurred in 11 patients (58%) in part 1 and 6 patients (25%) in part 2. All patients had a skin-related toxicity (no grade 4 events). Objective response rates were 46% in part 1 and 42% in part 2. Disease control rates were 74% in part 1 and 79% in part 2. Median progression-free survival (95% confidence interval) was 5.6 months (4.4-8.3 months) for part 1 and 10.9 months (7.7-22.5 months) for part 2. Median overall survival (95% confidence interval) was 17 months (13.7 months to not estimable) for part 1 and 22.5 months (14.4 months to not estimable) for part 2.. In patients with mCRC, panitumumab/IFL was not well tolerated. Panitumumab/FOLFIRI was well tolerated, showed promising activity, and is undergoing further investigation.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Panitumumab; Vitamin B Complex

To compare the use of capecitabine plus oxaliplatin (CAPOX) with infusional fluorouracil (FU)/folinic acid plus oxaliplatin (FUFOX) as first-line therapy for patients with metastatic colorectal cancer (MCRC).. A total of 474 patients with MCRC received either CAPOX (capecitabine 1,000 mg/m2 bid, days 1 to 14 plus oxaliplatin 70 mg/m2 days 1 and 8, repeated every 22 days) ) or FUFOX (oxaliplatin 50 mg/m2 followed by leucovorin 500 mg/m2 plus FU 2,000 mg/m2 as a 22-hour infusion days 1, 8, 15, and 22, repeated every 36 days). The primary end point was progression-free survival (PFS). Secondary end points were response rate (RR), overall survival (OS), time to treatment failure, and toxicity. The study was designed to determine noninferiority for the CAPOX regimen.. Median PFS was 7.1 months in the CAPOX arm and 8.0 months in the FUFOX arm (hazard ratio [HR], 1.17; 95% CI, 0.96 to 1.43; P = .117). Median OS was 16.8 months (CAPOX) and 18.8 months (FUFOX; HR, 1.12; 95% CI, 0.92 to 1.38; P = .26). Overall RRs were 48% for CAPOX (95% CI, 41% to 54%) and 54% for FUFOX (95% CI, 47% to 60%). Both regimens were generally well tolerated, although there was a significantly higher incidence of grade 2/3 hand-foot syndrome (HFS) in the CAPOX arm (P = .028).. CAPOX resulted in a slightly inferior efficacy than FUFOX. With respect to PFS, the best estimate of the HR of 1.17 was within the prespecified equivalence range. However, a relevant inferiority cannot be excluded. Both regimens were generally well tolerated but there was a significantly higher rate of grade 2/3 HFS in the CAPOX arm.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

Nasal natural killer (NK) cell lymphoma that showed distant metastases generally showed an poor prognosis. We described a group of patients with these atypical presentation and that were treated with an intensive, short chemotherapy/radiotherapy regimen.. Sixty-one patients fulfilled the criteria for NK cell lymphoma with distant metastases and all have very poor prognostic factors: high clinical risk, multiple extranodal presentation and bulky disease (tumor mass >10 cm). They were treated with CMED (cyclophosphamide 2000 mg/m(2), iv, day 1, methotrexate 400 mg/m(2), iv, day 1(with leucovorin rescue), etoposide 400 mg/m(2) twice and dexametasone 40 mg daily for 4 days). If complete response (CR) was observed, they were received adjuvant radiotherapy (50 Gy) to nasal region. Patients with failure were treated with different salvage treatments.. Forty nine patients achieved CR and 12 were considered failure, all patients that were failure and nine that relapse die secondary to tumor progression. Median follow-up were 46 months (range 34-68 months). Median has not been observed in relapse-free survival (RFS) and overall survival (OS). Actuarial curves at 5 years showed that RFS was 81% and OS was 65%. Treatment was well tolerated.. Nasal NK cell lymphoma with distant metastases is considered an rare clinical entity, probably is under diagnosis because it has been included as stage III and IV in previous reports, that showed an very poor RFS and OS. The treatment herein report could achieve good response and outcome, but it is evident that more specific and aggressive therapy is necessary in these setting of patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Etoposide; Female; Humans; Killer Cells, Natural; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Nose Neoplasms; Radiotherapy, Adjuvant; Salvage Therapy; Survival Analysis; Treatment Outcome

Gefitinib, an orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, combined with chemotherapy, has shown efficacy as second-line treatment for advanced colorectal cancer (CRC). Gefitinib combined with FOLFOX6 (oxaliplatin plus folinic acid and 5-fluorouracil) was tested as a first-line therapy.. Patients with metastatic EGFR-positive CRC received gefitinib at a dose of 250 mg/day combined with simplified FOLFOX6. Gefitinib was continued as maintenance treatment in nonprogressing patients. Responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and adverse events were assessed with the National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale.. A total of 56 patients were recruited. There were 26 men and 30 women, with a median age of 57.5 years. The Eastern Cooperative Oncology Group (ECOG) performance status was as follows: 0 in 39 patients, 1 in 12 patients, and 2 in 5 patients. Thirty-nine patients (69.6%) had stage IV disease at diagnosis, 92.9% had liver involvement, and 46.4% had > or =2 metastatic sites. All patients were evaluated for safety, and 53 were evaluated for response: 40 patients (71.4%; 95% confidence interval [95% CI], 57.8%-82.6%) had complete or partial responses, and 11 patients (19.6%) had stable disease. Median time to progression was 7 months (range, 2.1-33.0 months; 95% CI, 6.2-9.0 months). Radical surgery or thermoablation of metastatic sites was performed in 14 patients (25%). NCI-CTC grade 3-4 events occurred in 36 patients (64.3%): diarrhea in 9 patients (16.1%), and hematologic toxicity in 13 patients (23.2%). Four patients (7.1%) were withdrawn for drug-related adverse events.. The regimen has shown promising efficacy with manageable toxicity as a first-line treatment for patients with advanced CRC.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diarrhea; Disease Progression; ErbB Receptors; Female; Fluorouracil; Gefitinib; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Patient Dropouts; Quinazolines; Time Factors; Treatment Outcome

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against apoptosis. We raised the hypothesis that elevated tumor tissue levels and thereby plasma levels of TIMP-1 would predict resistance to apoptosis-inducing chemotherapy.. Ninety patients with metastatic colorectal cancer were included in the study. Plasma TIMP-1 and serum carcinoembryonic antigen (CEA) were measured in samples obtained before the first cycle of chemotherapy.. Analysis of best objective response (complete or partial response versus stable or progressive disease) showed that patients with low plasma TIMP-1 had higher probability of obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI), 1.4-8.5, P=0.007]. CEA treated as a continuous variable was also a statistically significant predictor of no response (OR, 1.3; 95% CI, 1.0-1.7, P=0.02, area under the curve 0.66) but much less so. Plasma TIMP-1 was the only significant covariate in a multivariable analysis of best objective response (OR, 3.6; 95% CI, 1.4-9.5; P=0.001). Plasma TIMP-1 scored as a continuous variable on the log scale (log(e)) was significantly associated with overall survival [OS; hazard ratio (HR), 3.8; 95% CI, 2.4-5.9; P<0.0001] and with time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P=0.048). Multivariable analysis showed that plasma TIMP-1 was significant for OS when including routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P<0.0001). A multivariable analysis including TTP instead of OS showed that only plasma TIMP-1 was retained in the model (HR, 1.5). CEA was not significantly associated with TTP or OS when TIMP-1 was included in the model.. This study shows that plasma TIMP-1 levels are significantly and independently associated with objective response, TTP, and OS in patients with metastatic colorectal cancer receiving combination chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Carcinoembryonic Antigen; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Odds Ratio; Rectal Neoplasms; Survival Analysis; Tissue Inhibitor of Metalloproteinase-1; Treatment Outcome

This phase II trial was performed to evaluate the efficacy and tolerability of oral tegafur-uracil (UFT) with leucovorin (LV) combined with intravenous (i.v.) irinotecan every 3 weeks (TEGAFIRI) as first-line treatment for patients with metastatic colorectal cancer (mCRC). Patients received oral UFT 250 mg m(-2) day(-1) and LV 90 mg day(-1) in three divided daily doses for 14 days followed by a 1-week rest and i.v. irinotecan 250 mg m(-2) as a 90-min infusion every 3 weeks. Tumour responses, assessed every two cycles using RECIST criteria, were reviewed by an independent review committee. In 52 evaluable patients, the best overall response rate was 33% (95% confidence intervals (CI) 20-47%; 1 complete and 16 partial responses). The median time to progression was 5.4 months (95% CI 3.02-7.52 months) and median overall survival was 14.9 months (11.73-17.97 months). A total of 307 cycles were administered, with a median number of five cycles per patient (range: 1-10). The most common grade 3/4 toxicities were neutropenia (25% of patients), diarrhoea (22%), vomiting (11%) and anaemia (11%). The TEGAFIRI regimen is a feasible, well-tolerated and convenient treatment option for patients with non-resectable mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Tegafur; Treatment Outcome; Uracil

In the OPTIMOX1 trial, previously untreated patients with advanced colorectal cancer were randomly assigned to two different schedules of leucovorin, fluorouracil, and oxaliplatin that were administered until progression in the control arm or in a stop-and-go fashion in the experimental arm. The randomly assigned treatment groups did not differ significantly in terms of response rate, progression-free survival, and overall survival (OS). However, the impact of oxaliplatin reintroduction on OS was potentially masked by the fact that a large number of patients did not receive the planned oxaliplatin reintroduction or received oxaliplatin after second-line therapy in both treatment groups.. A Cox model was fitted with all significant baseline factors plus time-dependent variables reflecting tumor progression, reintroduction of oxaliplatin, and use of second-line irinotecan. A shared frailty model was fitted with all significant baseline factors plus the number of lines of chemotherapy received by the patient and the percentage of patients with oxaliplatin reintroduction in the center. An adjusted hazard ratio (HR) was calculated for three reintroduction classes (1% to 20%, 21% to 40%, and > 40%), using centers with no reintroduction (0%) as the reference group.. Oxaliplatin reintroduction had an independent and significant impact on OS (HR = 0.56, P = .009). The percentage of patients with oxaliplatin reintroductions also had a significant impact on OS. Centers in which more than 40% of the patients were reintroduced had an adjusted HR for OS of 0.59 compared with centers in which no patient was reintroduced.. Oxaliplatin reintroduction is associated with improved survival in patients with advanced colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Proportional Hazards Models; Survival Rate; Treatment Outcome

Our objectives were to determine response rate, time to progression, overall survival and tolerability of novel combination chemotherapy, consisting of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin in advanced previously untreated colorectal cancer. Thirty-eight patients with advanced colorectal cancer were treated at Sylvester Comprehensive Cancer Center, University of Miami, from 2000 to 2004, and received weekly intravenous infusion of irinotecan at 110 mg/m with a combination of 120 mg/kg floxuridine and 500 mg/m leucovorin administered as a 24-h continuous intravenous infusion. The treatment cycle consisted of 4 weeks of consecutive therapy followed by 2 weeks of rest. Five (13%) patients achieved complete response, 10 (26%) patients achieved partial response, 17 (45%) patients attained stable disease and six (16%) patients progressed. The overall response rate was 39% in this study. This chemotherapy regiment was well tolerated; the most common grade 3 toxicities were neutropenia (16%), anemia (16%), vomiting (24%), diarrhea (16%), and hand-and-foot syndrome (26%). The median time to progression was 11.5 months (347.5 days) with 95% confidence intervals of 6.8-12.9 months (206-389 days). The time to progression ranged from 1.8 to 34 months. The median survival of the patients in this trial was 31.28 months (952 days) with a confidence interval of 20.9-38.0 months (629-1141 days). Intravenous infusion of floxuridine and leucovorin is beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged time to progression and overall survival with acceptable tolerability and manageable toxicity profile.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Floxuridine; Hematologic Diseases; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Rate

Randomized studies have shown that irinotecan (CPT-11) extends survival in metastatic colorectal cancer patients when administered in second-line and when added to fluorouracil (FU) plus leucovorin (LV) in first-line therapy of metastatic colorectal cancer. When this study was initiated, FU plus LV was standard adjuvant treatment for stage III colon cancer. We evaluated the efficacy and safety of weekly bolus CPT-11 plus FU plus LV in the treatment of patients with completely resected stage III colon cancer.. A total of 1,264 patients were randomly assigned to receive either standard weekly bolus FU plus LV regimen or weekly bolus CPT-11 plus FU plus LV. The primary end points of the study were overall survival (OS) and disease-free survival (DFS).. Treatment arms were well-balanced for patient characteristics and prognostic variables. There were no differences in either DFS or OS between the two treatment arms. Toxicity, including lethal toxicity, was significantly higher on the CPT-11 plus FU plus LV arm.. The addition of CPT-11 to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Treatment Outcome

To evaluate clinical characteristics and survival outcomes among patients with locally advanced or metastatic colorectal cancer who achieve a complete response (CR) to systemic treatment either alone or with multimodality approach.. Data were collected retrospectively from CRC patients enrolled onto the phase III trial N9741, a National Cancer Institute-funded and Gastrointestinal Cancer Intergroup-sponsored study coordinated by the North Central Cancer Treatment Group. Patients were randomly assigned to combinations of oxaliplatin, fluorouracil (FU)/leucovorin (LV) and irinotecan. The three treatment arms consist of IFL (irinotecan + FU/LV), FOLFOX4 (oxaliplatin + FU/LV), and IROX (irinotecan + oxaliplatin). Median follow-up was 42.6 months.. Sixty-two (4%) of 1,508 patients had a CR to chemotherapy alone, and an additional 32 (2%) had a CR after multimodality treatment. Factors associated with achieving CR with systemic chemotherapy alone included FOLFOX4 treatment, patients with assessable disease, or a single site of metastasis. Continuing protocol treatment beyond two cycles after documentation of CR was not associated with improved survival. The rate of curative intent resection was significantly higher for patients treated with oxaliplatin-containing regimens (P = .02). Median survival was similar between patients with CR after chemotherapy alone (44.3 months) or after multimodality approach (47.4 months; P = .81).. FOLFOX4 was more likely to produce a CR than were IFL or IROX. Oxaliplatin regimens were more likely to result in successful surgical resections. Patients who have CR to systemic chemotherapy alone can achieve impressive survival outcomes similar to those seen among patients who attained a CR status after multimodality treatment.

Topics: Aged; Antineoplastic Agents; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Remission Induction; Retrospective Studies; Treatment Outcome

The objective was to evaluate the efficacy and toxicity of leucovorin plus 5-fluorouracil combined with oxaliplatin (modified FOLFOX regimen) every 2 weeks on previously untreated advanced colorectal cancer patients in the Chinese population. Fifty-one inpatients were enrolled to receive 85 mg/m oxaliplatin intravenously over a 2- h period on day 1, together with 400 mg/m2 leucovorin over 2- h, followed by a 46-h infusion of 5-fluorouracil at 2600 mg/m2 every 2 weeks. Treatment was given until progression or unmanageable toxicity ensued. In all, 51 patients received three or more oxaliplatin doses and a median of nine treatment cycles (range 3-16 cycles). Of the 51 eligible patients, two complete responses and 22 partial responses were observed for an overall response rate of 47.0% (95% confidence interval 35-64%). Median progression-free survival was 7.7 months (95% confidence interval 6.8-8.6) and median overall survival was 15.0 months (95% confidence interval 13.1-16.9). Toxicities were mild: five patients (9.8%) reported grade 3-4 neutropenia, 33 patients (64.8%) experienced grade 1-3 neurotoxicity and only six patients (11.8%) experienced grade 3 neurotoxicity. The leucovorin plus 5-fluorouracil combined with oxaliplatin (modified FOLFOX) regimen is active and well tolerated in patients with previously untreated advanced colorectal cancer in the Chinese population.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

An economic evaluation of the irinotecan, leucovorin, 5-fluorouracil (FOLFIRI) combination versus the irinotecan, oxaliplatin, leucovorin, 5-fluorouracil (FOLFOXIRI) regimen in patients with metastatic colorectal cancer was performed in the context of a randomised phase III study.. The trial did not find any differences in efficacy and, therefore, a cost-minimisation analysis was undertaken. Treatment cost accounts for the administration of first and second line chemotherapy, for concomitant medications, for laboratory and other examinations and hospitalisations due to treatment side effects. Unit prices used reflect 2006 and are common among NHS hospitals in Greece.. The mean total cost of therapy in the FOLFOXIRI group (18,344 euros, 95% CI: 16,951 euros-19,776 euros), was significantly higher than the FOLFIRI group (12,201 euros, 95% CI: 11,011 euros-13,427 euros). Mean chemotherapy cost of the FOLFOXIRI group (9016 euros; 95% CI: 8338 euros-9669 euros) was significantly higher than that of the FOLFIRI group (4830 euros; 95% CI: 4435 euros-5231 euros). The next largest component of cost involves second line drugs, where the average cost per patient was 3306 euros (95% CI: 2479 euros-4237 euros) in the FOLFIRI group and 3996 euros (95% CI: 3196 euros-4892 euros) in the FOLFOXIRI group. The cost of hospitalisations was 1814 euros (95% CI: 1672 euros-1954 euros) in the first group and 2663 euros (95% CI: 2469 euros-2859 euros) in the second. The rest of the components represent a small part of the total cost and there are no differences in the two groups.. The combination of irinotecan, leucovorin, 5-fluorouracil has the same effectiveness as the combination of irinotecan, oxaliplatin, leucovorin, 5-fluorouracil in patients with metastatic colorectal cancer, nonetheless it is associated with a much lower overall treatment cost and it should be the preferred treatment regimen in this context.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Cost of Illness; Fluorouracil; Greece; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

This study assessed the clinical activity and safety of twice-weekly paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin (TP-HDFL) in patients with recurrent or metastatic esophageal squamous cell carcinoma. The regimen, composed of paclitaxel 35 mg/m 1-h intravenous infusion on days 1, 4, 8 and 11; cisplatin 20 mg/m 2-h intravenous infusion on days 2, 5, 9 and 12; and 5-flourouracil 2000 mg/m and leucovorin 300 mg/m 24-h intravenous infusion on days 5 and 12; repeated every 21 days. Forty-one patients (median age 51), 15 with de-novo metastatic disease and 26 with recurrent disease, were enrolled. Grades 3-4 neutropenia, leukopenia and diarrhea occurred in 37.8, 29.4 and 14.2% of cycles, respectively. One patient died of invasive fungal infection. Three complete responses, 13 partial response and 13 stable diseases were observed. The intent-to-treat response rate was 39.0% (95% confidence interval: 24-54). The median progression-free and overall survival were 6.3 and 8.9 months (range 1-50+), respectively. Twice-weekly TP-HDFL has the activity and toxicity profile similar to the previously reported same three-drug combination for advanced esophageal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Disease-Free Survival; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel

The current prospective study sought to trace the incidence and severity of oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical and electrophysiological pattern.. Twenty-five adult patients scheduled to be treated with 12 courses of the oxaliplatin-based regimen, FOLFOX-4, for metastatic colon cancer participated in this study. Patients were clinically and electrophysiologically monitored at baseline and followed-up during chemotherapy. The severity of OXLIPN was summarized by means of a modified Total Neuropathy Score (TNS).. Evidence of OXLIPN was disclosed in 16 of the 25 patients (64%). The mean TNS values for patients manifesting some grade of OXLIPN were 13.9 +/- 5.8 (range 7-28). All longitudinal comparisons concerning the motor conduction parameters failed to reach significance. By contrast, comparisons of the median changes at baseline and each of the follow-up studies revealed significant decrease in all sensory action potentials examined.. Our results indicate that the majority of patients treated with the FOLFOX-4 regimen would manifest an axonal, predominately sensory peripheral neuropathy, of mild to moderate severity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colonic Neoplasms; Electrophysiology; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Motor Neurons; Neoplasm Metastasis; Neurons, Afferent; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Severity of Illness Index

Two consecutive studies have evaluated the efficacy of oxaliplatin combined with the Nordic bolus schedule of 5-fluorouracil and folinic acid as first-line treatment in metastatic non-resectable colorectal cancer. One hundred and twelve patients were followed after end of first-line treatment and any secondary therapy registered. Fifty-three patients (47%) did not receive second-line irinotecan-based chemotherapy. The main reason was too poor performance status (59%). These patients had a median survival of only 1.7 months after progression of first-line therapy. The best predictive factors at start of first-line chemotherapy for receiving later second-line chemotherapy were performance status and alkaline phosphatase level. Fifty-nine patients (53%) received irinotecan-based second-line therapy. Four (7%) patients had a partial response, and 28 (52%) had stable disease. Median progression-free survival after second-line chemotherapy was 4.1 months and median survival 9.5 months. Median survival after first-line chemotherapy and secondary liver surgery was 34 months and five-year disease-free survival 8%. Survival among patients receiving both first- and second-line chemotherapy was 20.8 months, but only 8.9 months in patients not receiving second-line irinotecan-based chemotherapy. Poor performance status or elevated alkaline phosphatase level at start of first-line chemotherapy predicts whether second-line chemotherapy will be given or not.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Analysis

Tegafur is an oral fluorouracil prodrug used in the treatment of colorectal cancer. The aim of this phase II, crossover, bioequivalence study was to compare the pharmacokinetics (primary objective) and tolerability (secondary objective) of tegafur-uracil (UFT) given as three daily doses (tid, reference schedule) with those obtained using a more convenient schedule of two daily doses (bid, new schedule).. Twenty-one patients with metastatic colorectal cancer (median age 63 years) received the same oral daily dose of UFT (300 mg/m(2)/day) plus leucovorin (90 mg/day) divided into two or three daily doses. Patients were randomised to receive the first cycle either tid (12 patients) or bid (9 patients). The eligibility criteria included an Eastern Co-operative Oncology Group performance status of < or =1 and adequate bone-marrow, hepatic and renal function. The pharmacokinetics of uracil, fluorouracil and tegafur (high-performance liquid chromatography assays) were evaluated at steady state over 24 hours (area under the plasma concentration-time curve from 0 to 24 hours [AUC(24)], minimum plasma concentration [C(min)] and maximum plasma concentration [C(max)]). The pharmacokinetic parameters were analysed after logarithmic transformation according to a general linear model.. The AUC(24)values of fluorouracil (p < 0.0001), uracil (p < 0.0001) and tegafur (p = 0.058) were greater with the bid schedule than the tid schedule. The bid : tid AUC(24) ratio (90% CI) was 1.8 (1.55, 2.10) with fluorouracil, 2.0 (1.59, 2.57) with uracil and 1.2 (1.02, 1.36) with tegafur, indicating that the bid and tid schedules were not bioequivalent. No major toxicity (grade 4) was reported, and grade 3 adverse events accounted for 9% of the total adverse events. Intra-patient comparison of the maximum toxicity grade did not demonstrate a significant difference between the bid and tid schedules (p = 0.18).. A 2-fold increase in the fluorouracil and uracil AUC values was observed with UFT administered bid compared with tid, without a significant impact on tolerability, suggesting that the more convenient bid schedule may improve the UFT therapeutic index.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biological Availability; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Cross-Over Studies; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prodrugs; Sex Factors; Tegafur; Therapeutic Equivalency; Uracil

Second-line treatment of relapsed or metastatic colorectal cancer (CRC) after failure of treatment with a fluoropyrimidine is composed of oxaliplatin in combination with a fluoropyrimidine or an irinotecan-containing regimen. Cisplatin and gemcitabine are synergistic in preclinical studies, as is 5-fluorouracil (5-FU) combined with either agent. Fixed-rate infusional gemcitabine is more effective than bolus administration in animal models.. A 2-stage phase II trial was conducted to assess the efficacy (the primary endpoint was response rate) and safety of a regimen consisting of 5-FU 400 mg/m(2) as an intravenous bolus at the middle of a 60-minute infusion of leucovorin 100 mg/m(2), followed by gemcitabine 800 mg/m(2) over 80 minutes, and cisplatin 20 mg/m(2) over 15 minutes. Treatment was repeated weekly for 3 weeks followed by a 1-week rest. Patients with advanced CRC were eligible if they had experienced treatment failure with fluoropyrimidine-based therapy.. Nineteen patients were enrolled. The median age was 60 years; 15 patients were men and 4 were women. Twelve patients had colon cancer and 7 had rectal cancer. Sites of metastasis were as follows: liver (n = 10), lung (n = 8), skin (n = 1), and non-regional lymph nodes (n = 1). All patients had an Eastern Cooperative Oncology Group performance status of 0/1. A total of 44 cycles of chemotherapy were delivered (median, 2 cycles; range, 1-5 cycles). One patient exhibited a partial response (5%), 8 had stable disease (42%), and 5 experienced disease progression (26%); another 5 patients were nonevaluable (26%). The median time to progression was 8 weeks and median survival was 36 weeks. Grade 3/4 toxicities were as follows: diarrhea (n = 1), dyspnea (n = 1), pneumonia (n = 1), neutropenia (n = 2), and thrombocytopenia (n = 1).. Despite acceptable toxicity and a reasonable overall survival, the combination of 5-FU/leucovorin/gemcitabine/cisplatin does not seem to improve current standard therapy in the second-line treatment of patients with CRC in whom a first-line fluoropyrimidine-containing regimen has failed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Deoxycytidine; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Survival Analysis

Patients older than 75 years of age are usually excluded from metastatic colorectal cancer randomized studies. The OPTIMOX1 study evaluated FOLFOX7, a simplified (s) leucovorin (LV) and 5-fluorouracil (5FU) regimen (sLV5FU2) with high-dose oxaliplatin, in a new oxaliplatin stop-and-go strategy. An exploratory cohort of patients aged 76 to 80 years was included in the study.. In all, 620 previously untreated patients were randomized between FOLFOX4 until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B).. A total of 37 patients aged 76 to 80 years were included, 20 in arm A and 17 in arm B. The overall response rate (ORR) was 59.4%, comparable to younger patients (59%). Median progression-free survival (PFS) was 9.0 months and median overall survival (OS) was 20.7 months. These results did not differ from that in younger patients < or =75 years in the OPTIMOX1 study with PFS 9.0 months (P = .63) and OS 20.2 months (P = .57). They experienced slightly more grade 3 of 4 toxicity than younger patients: 65% versus 48% (P = .06), mainly with more neutropenia (41% vs 24%, P = .03) and neurotoxicity (22% vs 11%, P = .06). Tolerability, however, was manageable and no toxic death occurred in this elderly population.. The efficacy of FOLFOX-based treatment was maintained in patients >75 years with both FOLFOX regimens. The oxaliplatin stop-and-go management strategy performed well in this population.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Survival Rate

Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC.. Pacl was infused at a fixed dose of 150 mg/m2 on day 1. UFT, at doses escalated by 50 mg/m2 starting from 200 mg/m2 . day, and LV, at a fixed dose of 90 mg/day, were given orally every 8 h for 11 days (days 3-13). Cohorts of at least 3 patients were treated at each dose level, and if 1 experienced dose-limiting toxicity (DLT), a maximum of 3 additional patients were added at the same dose level. MTD was reached if 2 out of the 6 patients experienced DLT.. Sixteen patients were enrolled in the study. The most important toxicity observed was hematological. Nonhematological toxicities were paresthesia and myalgia, asthenia, nausea, and mucositis. DLT occurred in only 1 patient (grade 3 hepatic toxicity).. The recommended dose for a subsequent phase II trial is Pacl 150 mg/m2 on day 1, and UFT 300 mg/m2 and LV 90 mg on days 3-13, every 2 weeks.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Drug Administration Schedule; Drug Screening Assays, Antitumor; Female; Humans; Leucovorin; Maximum Tolerated Dose; Middle Aged; Models, Theoretical; Neoplasm Metastasis; Paclitaxel; Tegafur; Uracil

This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor-expressing metastatic colorectal cancer (mCRC).. The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m(2) during week 1, then 250 mg/m(2) weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1; leucovorin 200 mg/m(2) on days 1 and 2, followed by fluorouracil 400 mg/m(2) bolus then 600 mg/m(2) intravenous infusion during 22 hours on days 1 and 2).. The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated.. Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.

Topics: Adult; Aged; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Mice; Mice, Inbred BALB C; Middle Aged; Neoplasm Metastasis; Neoplasm Transplantation; Organoplatinum Compounds; Patient Compliance; Transplantation, Heterologous

1) To confirm the efficacy of irinotecan plus folinic acid/continuous 5-fluorouracil as bimonthly FOLFIRI regimen in metastatic colorectal cancer patients. Efficacy evaluations will include response rate, duration of response, and survival. 2) To evaluate safety profiles on patients receiving this combination.. Nineteen patients with metastatic colorectal cancer received 180 mg/m2 intravenous (iv) day 1 of irinotecan, 200 mg/m2 iv of folinic acid, 400 mg/m2 iv bolus days 1 to 2, 5-fluorouracil (5-FU), and 600 mg/m2 iv 5-FU infusion over 22 hours, days 1 to 2. Treatment was repeated every two weeks and one cycle contained three fortnightly administrations. Sites of disease were liver in nine patients, lungs in three patients, bowels in four patients, lymph nodes in three patients, and peritoneum in two patients. Two patients had > 1 metastatic site. Previous treatments included adjuvant chemotherapy in seven cases and front-line chemotherapy for advanced disease in one case.. A median of six treatment cycles was completed (range, 2-13 cycles). All patients were assessable for toxicity and 16 patients were evaluable for treatment response. The non-hematological toxicity was mild. Most had grade 1 or 2. Only one patient experienced grade 3 fatigue and anorexia, and discontinued chemotherapy after the second cycle. There were no cases with grade 4 toxicity. Fourteen patients had at least grade 2 alopecia. The most common hematological toxicity was neutropenia. Grade 3 and 4 neutropenia were observed in three and two patients, respectively. There was no case of febrile neutropenia. Based on intention to treat analysis, there were no complete responses (CR), five (26.3%) partial response (PR), and 11 (57.9%) stable disease. With the median follow-up of 6.6 months, the median time to disease progression was 4.7 months and the median survival time was 10.6 months.. Bimonthly irinotecan in combination with folinic acid and 5-fluorouracil was active with acceptable toxicities and a prolonged survival time in pretreated colorectal cancer. Additional trials to define the optimal dose and schedule of treatment are justified.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies; Survival; Time Factors; Treatment Outcome

To evaluate the tolerability and effectiveness of uracil-tegafur (UFT) with leucovorin (LV) in the treatment of elderly patients with advanced colorectal cancer.. Patients > or = 75 years of age with previously untreated colorectal cancer were eligible for this phase II, single-arm, open-label, multicenter cooperative group clinical trial. UFT 100 mg/m2 plus LV 30 mg orally every 8 hours for 28 days every 35 days was administered until progression.. Fifty-eight patients were enrolled between June 2000 and July 2001, and 55 were treated. The median age of treated patients was 81 years (range, 75 to 90 years), 26 patients were (47%) women, and 80% had good performance status (0 to 1). The observed overall response rate was 22% (95% CI, 11.8% to 35.0%). The estimated median overall survival time was 13.0 months (95% CI, 9.6 to 17.4 months), and median progression-free survival time was 4.6 months (95% CI, 2.6 to 6.7 months). Among the 56 treated patients (including one ineligible patient), 31 (55%) experienced grade 3 to 4 toxicities, most commonly diarrhea (25%) and GI toxicity (36%), with patients older than 85 years of age at highest risk.. The results of this trial support the efficacy of oral UFT/LV in elderly patients with colorectal cancer. The regimen is tolerated moderately well overall, particularly as compared with other fluoropyrimidine regimens, although there is increased GI toxicity in the most elderly. These results suggest that studies using newer oral fluoropyrimidine analogs should be investigated in this patient population.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Humans; Leucovorin; Male; Neoplasm Metastasis; Tegafur; Uracil

It has been demonstrated that the 3-weekly PELF regimen is superior to FAM and FAMTX in advanced gastric cancer. The aim of this multicentric phase II study was to evaluate the efficacy and tolerability of a PELF regimen, given every 2 weeks as a first-line therapy in patients with unresectable or metastatic gastric carcinoma.. Fifty-nine patients were treated with the following schedule: cisplatin (40 mg/m2, day 1), epirubicin (30 mg/m2, day 1), 5-fluorouracil (400 mg/m2 bolus, followed by 600 mg/m2, 22 h continuous infusion, day 1 and 2) and folinic acid (100 mg/m2, 2-h infusion, day 1 and 2). G-CSF (5 microg/kg) was administered on day 6, 8, 10, and 12. Cycles were repeated every 2 weeks for a maximum of twelve courses.. Of the 52 evaluable patients, three (5.8%) complete responses, and 15 (28.8%) partial responses were observed, for an overall response rate of 34.6%. The median duration of response was 8 months. Nineteen patients had stable disease and 15 progressed on therapy. At a median follow-up of 12 months, the median time to progression was 8 months and the median survival duration was 13 months, with a 1-year survival rate of 53.5%. Grade 3 or 4 observed toxicities were: neutropenia in 26 patients (44%), thrombocytopenia in four patients (6.7%), and mucositis in seven patients (11.9%).. The bi-weekly PELF regimen seems to be feasible with an acceptable toxicity profile and an activity comparable to the 3-weekly schedule.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Stomach Neoplasms; Time Factors

The present study was conducted to evaluate activity and toxicity of the FLEC (folinic acid 100 mg/m2; 5-fluorouracil 1000 mg/m2; carboplatin 300 mg/m2; epirubicin 60 mg/m2) schedule as second-line treatment for progressive locally advanced or metastatic pancreatic cancer (LAMPC). FLEC was administered every 3 weeks with an angiographic catheter introduced into the tumor vascular bed. Thirty-two patients were enrolled. Twenty patients had a PS of 2. Twenty-five patients had metastatic disease to liver. Seven (21.9%) partial responses were observed (WHO criteria). Fifteen patients (46.9%) had stable disease and ten patients (31.2%) had progressive disease. The median OS from the diagnosis was 11.8 months. PS (p=0.0308) and pain (WHO scale, p=0.0222; analogic scale, p=0.0446) significantly improved after therapy. No patient discontinued treatment because of toxicity (NCI-CTC criteria). The current study shows that intraarterial chemotherapy is a good therapeutic option in second-line treatment of LAMPC.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carboplatin; Disease Progression; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Retrospective Studies; Time Factors; Treatment Outcome

To investigate the safety/tolerability of the EGFR-antibody cetuximab when added to irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) for first-line treatment in patients with metastatic colorectal cancer (mCRC).. Twenty-one patients with untreated, metastatic, EGFR-expressing CRC received cetuximab 400 mg/m(2) as an initial dose, and thereafter 250 mg/m(2) weekly. In addition, patients received infusional 5-FU (24 h) in two dose levels (1500 mg/m(2), low 5-FU group, n = 6 or 2000 mg/m(2), high 5-FU group, n = 15), plus FA at 500 mg/m(2) and irinotecan at 80 mg/m(2), weekly x6 q50d.. Twenty patients were assessable for tolerability after the first cycle. There were no dose limiting toxicities (DLTs) in the low 5-FU group and three DLTs (20%) in the high 5-FU group (two patients with diarrhea grade 3 and one patient with diarrhea grade 4). In the low 5-FU group all six patients received >80% of the planned dose. In the high 5-FU group, seven of 14 patients (50%) received < or =80% of the planned chemotherapy dose during the first cycle due to dosage reductions whilst treatment delays occurred in 10/14 patients. During the whole study period, the common grade 3/4 adverse events were acne-like rash (38%) and diarrhea (29%). Chemotherapy did not affect the pharmacokinetics of cetuximab determined at weeks 1 and 4. Fourteen patients (67%, 95% CI 47% to 87%) had a confirmed response, and six (29%) had stable disease. Median time to progression was 9.9 months [lower 95% confidence limit (CL) 7.9, upper 95% CL not reached]. Median survival time was 33 months (lower CL 20, upper CL not reached). Four patients received secondary surgery with curative intent, and a fifth was potentially eligible for surgery but declined.. Addition of cetuximab to weekly infusional 5-FU/FA plus irinotecan is safe and first data suggest a promising activity. The 5-FU dose of 1500 mg/m(2) is recommended for further studies.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease Progression; ErbB Receptors; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Neoplasm Metastasis

This phase II trial was performed to evaluate the efficacy and tolerability of a new combination of Uracil/Ftorafur (UFT)/leucovorin (LV) and oxaliplatin in patients (pts) with metastatic colorectal cancer (MCRC) who had not received prior chemotherapy for metastatic disease. Between February 2002 and October 2002, 64 patients received UFT 300 mg m(-2) day(-1) and LV 90 mg day(-1) from day 1 to day 14 combined with oxaliplatin 130 mg m(-2) on day 1, every 3 weeks. All patients were evaluable for safety analysis and 58 of 64 patients were eligible for efficacy. Responses were reviewed by an independent review committee. Of the 58 per-protocol defined assessable patients, 1 complete response and 20 partial responses were observed yielding a response rate of 34% (95% CI: 22-47). The median response duration was 8.74 months (range 1.6-14). The median time to progression and the median survival were 5.88 months (95% CI: 4.34-8.21) and 18.2 months (95% CI: 10-20.7), respectively. Diarrhoea and peripheral neuropathy were the most frequent and predictable toxicities. These events were reversible, noncumulative and manageable. Grade 3 diarrhoea occurred in only 11% of the patients. No grade 4 gastrointestinal toxicity was reported in the study. The incidence of grade 3/4 (National Cancer Institute Common Toxicity Criteria 2: NCI-CTC 2) peripheral neuropathy was 15%. Haematological toxicity was of mild to moderate intensity with 10% of the patients with Grade 3/4 neutropenia without any episode of complication. The TEGAFOX regimen, a new combination using UFT/LV and oxaliplatin every 3 weeks is feasible on an outpatient basis. The combination is safe and active and may offer a promising alternative to the intravenous route. Nevertheless this efficacy results should be confirmed by randomized phase III trials.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diarrhea; Female; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Peripheral Nervous System; Survival Analysis; Tegafur; Treatment Outcome; Uracil

Irinotecan or oxaliplatin combined with 5-fluorouracil (5-FU) +/- folinic acid (FA) has changed the treatment standards for metastatic colorectal cancer (CRC). The oxaliplatin and irinotecan combination has reported consistent activity. The purpose of this phase II study was to assess the efficacy and safety of the simultaneous administration of a triple chemotherapy combination of oxaliplatin, irinotecan, 5-FU bolus, and FA.. Eligible patients had metastatic CRC with no prior oxaliplatin or irinotecan-based chemotherapy. Treatment consisted of oxaliplatin 85 mg/m2 followed by irinotecan 150 mg/m2, repeated every 15 days, with 5-FU 500 mg/m2 bolus and FA 20 mg/m2 on days 1, 8, and 15. An early amendment suppressed the day 8 5-FU/FA.. Twenty-six eligible treated patients receiving 253 doses were assessed for toxicity. Myelosuppression was the most frequent toxicity; grade 3 to 4 neutropenia and febrile neutropenia occurred in 50% and 15% of patients, respectively. The treatment schedule modification, omitting the 5-FU dosing on day 8, considerably improved treatment compliance, reducing the incidence of febrile neutropenia, diarrhea, and asthenia. Among the 25 patients evaluable for efficacy, 10 had objective responses including 1 complete response (CR) (4%) and 9 partial responses (PR) (36%), giving an overall response rate of 40%. Median time to progression was 6.20 months [95% confidence interval (CI), 5.44-6.96]. Median overall survival was 12.95 months.. The administration of a triple combination produced promising objective responses with acceptable toxicity but does not seem to produce an evident benefit in time-related parameters.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

We conducted a phase II study to determine the activity and tolerability of weekly paclitaxel, 5-fluorouracil (5-FU) and folinic acid plus granulocyte colony-stimulating factor (G-CSF) support in anthracycline-pre-treated or -resistant metastatic breast cancer patients. The phase II study was designed following the Simon optimal-two stage method. Patients received paclitaxel 80 mg/m, folinic acid 10 mg/m and bolus infusion of 5-FU 300 mg/m every week plus G-CSF on day 3 for 24 consecutive weeks in the absence of disease progression. From May 1998 to May 2000, 51 patients entered the study. Patients received a median relative dose intensity of 97.5% (range 81-100%). No severe toxicities were observed. Seven patients (14%) experienced neutropenia grade 2. Seven patients (14%) experienced grade 2 anemia. Two patients (4%) experienced severe asthenia. Three out of 50 evaluable patients [6%, 95% confidence interval (CI) 2-12.6%] showed a complete response, whereas 23 (46%, 95% CI 32.2-59.8%) had a partial response, with an overall response rate of 52% (95% CI 38.2-65.8%). In addition, eight patients (15.7%) had stable disease. In the 13 patients untreated for metastatic disease, the overall response rate was 92.3% (CI 77.8-100), with one complete response and 11 partial responses (84.6% CI 65-100%). In the whole group, the median time to progression and overall survival were 8 (range 1-18) and 14 months (95% CI 11-17), respectively. Thus, in metastatic breast cancer patients pre-treated with anthracyclines, the weekly administration of paclitaxel, 5-FU and folinic acid with G-CSF support seems to be extremely tolerable and active.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel

We assessed a schedule alternating 4 FOLFOX and 4 FOLFIRI cycles in 39 patients with 5-FU resistant metastatic colorectal cancer. Patients alternatively received 4 FOLFOX-6 cycles (oxaliplatin 100 mg/m(2), leucovorin 200 mg/m(2) d1 followed by bolus 400 mg/m(2) 5-FU and by a 46-hour 2,400 mg/m(2) 5-FU infusion, every 2 weeks), and 4 FOLFIRI cycles (oxaliplatin replaced by irinotecan 180 mg/m(2) d1) until progression or limiting toxicity. Eigteen patients achieved an objective response (46.1 percent). Median progression-free and overall survivals were 8.8 and 18.7 months, respectively. Only 2 patients (5.1 percent) had Grade 3 oxaliplatin-related sensory-neuropathy. This schedule had so promising efficacy and safety.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

To analyze in a pilot study the association between the pharmacokinetics of chronomodulated administered oxaliplatin and non-hematological toxicity in patients with metastatic gastrointestinal cancer.. 16 patients received a 4-day chemotherapeutic regimen consisting of a 12-h chronomodulated infusion of oxaliplatin (25 mg/m2) followed by a 12-h chronomodulated infusion of 5-fluorouracil (750 mg/m2) and sodium folinate (150 mg/m2) daily. Plasma pharmacokinetics of oxaliplatin, measured as ultrafiltrable platinum, were determined.. Pharmacokinetics and non-hematological adverse events could be assessed in all patients included in the study. Pharmacokinetic parameters showed moderate interpatient variability. The occurrence of nausea and vomiting, but not diarrhea, was significantly associated with the pharmacokinetics of ultrafiltrable platinum. Thus, increased AUC values were observed in patients who experienced nausea or vomiting. No differences in pharmacokinetic parameters were found between patients with and without oxaliplatin-induced neurotoxicity or the other selected non-hematological toxicities.. The preliminary results in this pilot study suggest an association between pharmacokinetics of ultrafiltrable platinum and non-hematological toxicity such as nausea and vomiting. Furthermore, although the sample size is limited, systemic exposure to ultrafiltrable platinum appears to predict the risk of non-hematological toxicity in patients treated with chronomodulated oxaliplatin combined with 5-FU and FS.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Chronotherapy; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pilot Projects

Determine the toxicity, tolerability, and pharmacokinetics of SU5416, a vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, coadministered with bolus 5-fluorouracil (5-FU), leucovorin, and irinotecan (IFL) in untreated patients with metastatic colorectal cancer.. SU5416 (85 or 145 mg/m2) was administered twice weekly throughout a 6-week period along with standard IFL (4 weeks on/2 weeks off). Plasma samples were assayed for SU5416, irinotecan, and SN-38 by reverse-phase HPLC. Contrast enhanced, color Doppler sonography was performed on patients at the MTD to identify changes in tumor perfusion.. Eleven patients received treatment with SU5416 85 mg/m2 (n = 5) or 145 mg/m2 (n = 6). At 85 mg/m2, no DLTs were observed. At 145 mg/m2, grade 3 diarrhea and vomiting were observed during cycle 1; other grade 3 toxicities included fatigue, nausea, anorexia, anemia, pain, urinary retention, and hypertension. The pharmacokinetics of irinotecan and SN-38 were not altered by coadministration of SU5416. SU5416 pharmacokinetics were not altered by IFL. Contrast-enhanced, color Doppler sonography was performed on 2 patients and demonstrated reduced tumor perfusion after treatment in a patient who responded to treatment and increased perfusion in a patient who developed progressive disease. Three patients (27%) had confirmed partial responses, 2 patients (18%) had unconfirmed partial responses, and 4 patients (36%) had stable disease.. Twice weekly SU5416 can be administered with bolus IFL without unexpected toxicities or altering the pharmacokinetic behavior of the administered drugs. Changes in tumor blood perfusion can be detected by contrast-enhanced, color Doppler sonography. The further development of SU5416 was halted before this study was completed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Indoles; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pyrroles; Vascular Endothelial Growth Factor Receptor-2

The aim of the study was to evaluate the safety and efficacy of the raltitrexed/5-fluorouracil/levofolinic acid combination regimen as first-line chemotherapy for elderly patients with advanced/metastatic colorectal cancer.. Previously untreated patients with metastatic colorectal cancer received raltitrexed 2 mg/m(2) i.v. plus levofolinic acid and 5-fluorouracil according to the De Gramont' schedule given every 2 weeks as first-line chemotherapy. Patients were re-evaluated after six cycles and chemotherapy was continued up to tolerance or disease progression.. Seventy patients aged >/=65 years were accrued from 11 centers between September 2001 and July 2002. According to the intention-to-treat analysis, the overall response rate was 35% (95% CI 29.5% to 40.5%) including one complete response (1%) and 24 partial responses (34%). Twenty patients (31%) showed a stabilization of disease for a tumor growth control rate of 64% (95% CI 57% to 71%). The median overall survival was 12.5 months and the median time to disease progression was 6.5 months. No toxic deaths or allergic reaction were recorded. Grade 4 toxicities were non-existent. The main hematological toxicity was grade 3 neutropenia, which occurred in 9% of patients, and grade 3 anemia in only one case, while no case of graded 3 thrombocytopenia was observed. Grade 3 non-hematological toxicities were asthenia (11%), transient increase of transaminases (10%) and diarrhea (4%).. The results of this study suggest that the raltitrexed/5-fluorouracil/levolofinic acid combination is an effective and well tolerated regimen for the treatment of elderly patients with advanced colorectal cancer. Its ease of administration and patient's tolerance warrant further investigation over 5-fluorouracil/folinic acid regimens.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Quinazolines; Thiophenes

To evaluate the efficacy of Avastin in combination with irinotecan for metastatic colorectal cancer.. Ninety patients were randomly divided into 3 equal groups to receive Avastin plus irinotecan (group A), FOLFIRI (group B) and FOLFOX7 (group C) for two cycles, respectively. The response rate and changes in tumor maker levels were observed.. The tumor response rate was 43.3% in group A, 27.7% in group B and 30.0% in group C. The disease control rate (complete response+partial response+stable disease) was 80% in group A, 53.3% in group B and 50.0% in group C. Obvious changes in tumor marker levels were observed in the 3 groups after treatment, which were most conspicuous in group A (P<0.05).. The addition of Avastin to irinotecan chemotherapy results in significant improvement of clinical efficacy in patients with metastatic colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Treatment Outcome

We conducted two phase II trials evaluating the combination of 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) as first-line treatment in 74 metastatic colorectal cancer patients. Results were very promising with an overall response rate of 71% and 72%, a median PFS of 10.4 and 10.8 months and an overall survival of 26.5 and 28.4 months, respectively. A concern about the use of all three active agents up-front is the possibility that this might limit, after progression, disease control with second-line treatments. Therefore, we conducted the present analysis to evaluate the outcome of second-line treatments in these 74 patients.. Among the 71 patients so far progressed 54 (76%) received second line chemotherapy (23: FOLFIRI, 17: FOLFOXIRI, five: 5-FU protracted infusion, three: FOLFOX, three: 5-FU+MMC, two: CPT-11, one: CPT-11+LOHP, one: raltitrexed). Seventeen patients (24%) did not receive second line treatments: 10 because of deterioration of performance status (PS), four because of patient refusal and three because of death. Patients' characteristics at the time of second-line treatment were: M/F 36 of 18 patients, median age 64 yrs (range 44-75), ECOG PS>or=1 21 (39%) patients, multiple sites of disease 33 (61%) patients.. A median of 4.1 months of second-line chemotherapy per patient were administered (range 1-8). Overall response rate (52 out of 54 evaluable patients) was 33% and stable disease were 19 (37%). Median duration of response was 8.1 months. At a median follow up of 15.1 months from the start of salvage chemotherapy median PFS and overall survival were respectively 6.7 and 15.2 months.. First-line FOLFOXIRI does not impair the possibility to obtain objective responses and delay tumor progression with second line treatments containing the same agents used in first-line.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent.. In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy.. UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA7/TA7 compared with wild-type TA6/TA6. The response rate was also higher in TA7/TA7 patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA6/TA6. A nonsignificant survival advantage was observed for TA7/TA7 when compared with TA6/TA6 patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)x(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA7/TA7 genotype and a higher response rate, indicating that the polymorphism is functionally relevant.. The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Polymorphism, Genetic; Prospective Studies; Treatment Outcome

Patients with untreated advanced colorectal cancer were enrolled to this single arm phase II multi-center cooperative group trial of bevacizumab combined with IFL. The first 20 patients received irinotecan (125 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and leucovorin (20 mg/m(2)) weekly for four of six weeks and high-dose bevacizumab (10 mg/kg) every other week. Following a toxicity review of other trials using IFL, subsequent patients were enrolled at reduced doses of irinotecan (100 mg/m(2)) and 5-fluorouracil (400 mg/m(2)).. Of the 92 patients accrued to the study, toxicity data are available for 87 patients and efficacy data for 81 patients. At a median follow-up of 37.5 months, median overall survival is 26.3 months, median progression free survival is 10.7 months and 1-year survival is 85%. The overall response rate is 49.4% (6.2% complete responses). A reduction in the starting doses of irinotecan and 5-fluorouracil decreased the occurrence of vomiting, diarrhea and neutropenia related complications. Bleeding occurred in 37 patients; all events but two were grade 1 or grade 2. There were nine reports of grade 3 or grade 4 thrombo-embolic events. Hypertension of any grade occurred in 13% of patients and proteinuria was infrequent.. High-dose bevacizumab added to IFL is a well-tolerated and highly active regimen in patients with previously untreated metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Staging; Survival Analysis; Treatment Outcome

Treatment options for advanced or metastatic gastric cancer (A/MGC) are limited and inclusion of novel substances is necessary. Few studies have confirmed the activity and tolerability of the combination of oxaliplatin (OXA) and 5-fluorouracil (5-FU) modulated with leucovorin (LV) administrated to patients with A/MGC. The goal of current study was to evaluate the efficacy and toxicity of Folfox-4 regimen in patients with A/MGC.. Fifty-six patients were treated with Folfox-4 regimen. Treatment was continued until disease progression, unacceptable toxicity or until a patient chose to discontinue treatment. Responses to treatment and toxicity were recorded according to the WHO criteria and NCI toxicity criteria.. All patients were assessable for toxicity and response. Patients (71.4% male, 28.6% female) had a median age of 65 years (range, 28-78). All patients had histologically confirmed metastatic (89.3%) or advanced (10.7%) gastric cancer. Response was evaluated every 6 weeks; 1 complete (1.8%) and 23 (41.1%) partial remission were observed (overall response rate 42.9%). Twenty patients (35.7%) showed stable disease and 12 (21.4%) had a progressive disease. Median overall survival, time to progression and follow up were 10 months, 6 months, and 11.5 months, respectively. WHO grade 3 or 4 hematologic toxicities included leucopenia, neutropenia, thrombocytopenia, and anemia. No patient experienced neutropenic fever. Other grade 3/4 toxicities included nausea, vomiting, diarrhea, stomatitis, and anorexia. Three patients (5.3%) experienced grade 3 peripheral neuropathy. No treatment-related deaths were recorded.. Folfox-4 regimen is active and well tolerated in patients with advanced/metastatic gastric cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Stomach Neoplasms

Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. On the basis of sensitivity to previous treatment, 19 patients were considered as chemo-resistant and 14 patients as chemo-refractory. OXA 110 mg/m (over 2 h) and IRI 175 mg/m (over 1 h) were delivered on day 1, followed by LFA 250 mg/m (2-h infusion) plus 5FU 800 mg/m as intravenous bolus on day 2. Cycles were repeated every 2 weeks. A total of 348 cycles were delivered, with a median of nine cycles per patient (range, 1-12 cycles per patient). Five complete and 13 partial responses were reported on 40 assessable patients, giving a response rate of 45% [95% confidence interval (CI), 29-62%]; eight of 19 (42%) resistant patients and five of 14 (36%) refractory patients achieved a major response, which was also obtained in four of eight (50%) patients pretreated with IRI and in three of eight (38%) patients pretreated with OXA. Grade 3 or higher neutropenia occurred in 68% of patients, but febrile neutropenia or infections affected only seven (17%) patients. No episodes of grade 3 or higher thrombocytopenia or anemia were recorded. Occurrence of severe non-hematologic toxicities by patients were: diarrhea, 34%; vomiting, 17%; peripheral cumulative neuropathy, 15%; stomatitis, 10%; acute cholinergic syndrome, 7%. Actually delivered dose intensities of all three drugs resulted in about two-thirds of the planned ones. After a follow-up of 39 months, median progression-free survival was 7.5 months. Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Humans; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

To evaluate the efficacy and tolerability of the metastatic irinotecan plus oxaliplatin (MIROX) strategy (adjuvant FOLFOX-7 followed by FOLFIRI), in patients with resectable metastatic colorectal cancer.. Forty-seven patients with resectable metastases of colorectal cancer were prospectively enrolled onto this study. Treatment consisted of six cycles of leucovorin 400 mg/m(2), oxaliplatin 130 mg/m(2) in a 120-minute infusion, and fluorouracil (FU) 2,400 mg/m(2) in a 46-hour infusion, every 2 weeks (FOLFOX-7), followed by six cycles of leucovorin 400 mg/m(2), irinotecan 180 mg/m(2) in a 90-minute infusion, bolus FU 400 mg/m(2), and FU 2,400 mg/m(2) as a 46-hour infusion, every 2 weeks (FOLFIRI). Surgery was performed before chemotherapy in 25 patients and after six cycles of FOLFOX-7 in 22 patients (six cycles of FOLFIRI were administered after surgery).. All but one of the patients underwent curative surgery. Two patients refused postoperative chemotherapy. Tolerability was generally good. The main toxicities were grade 3 to 4 neutropenia (13%) and thrombocytopenia (11%); no febrile neutropenia or bleeding occurred, and there were no deaths caused by toxicity. Two pathologically confirmed complete responses and 15 partial responses were obtained with FOLFOX-7 in the 22 patients who received this regimen before surgery (overall response rate, 77%; 95% CI, 68 to 86). The median disease-free survival time was 21 months; the median overall survival has not yet been reached. The 2-year overall and disease-free survival rates were 89% and 47%, respectively.. The MIROX strategy is feasible and well tolerated by patients with resectable metastatic colorectal cancer. Progression-free and overall survival rates are promising, with a median of 38 months of follow-up. This strategy currently is being compared with the leucovorin and FU regimen in a phase III trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prospective Studies; Treatment Outcome

Despite recent improvements in the treatment of metastatic colorectal cancer, few patients are cured and the response rates to second-line treatments are poor. Onyx-015, an oncolytic virus, was administered to patients with metastatic colorectal cancer by hepatic artery infusion. No dose-limiting toxicities were observed in the phase I/II studies. Onyx-015 can kill tumor cells by mechanisms that are distinct from chemotherapeutic agents and may therefore have activity among patients who have failed first-line chemotherapy. The 24 patients included in this analysis had failed first-line therapy with 5-FU/leucovorin, 79% of the patients failed two or more regimens and 58% had failed treatment with Irinotecan. Despite the extensive prior therapy, the median survival of these patients was 10.7 months, 46% were alive at 1 year and two patients (8%) had partial responses. In all, 11 patients (46%) had stable disease at the completion of the four planned viral treatments (3 months). The median survival of this group of patients was 19 months, suggesting that stable disease may be an important predictor of benefit with oncolytic viruses. Eight of the 11 patients with stable disease at 3 months demonstrated a unique radiographic pattern of transient enlargement of tumor masses (10-48%) after the initial infusions of Onyx-015, followed by radiographic evidence of extensive tumor necrosis and regression. The initial enlargement and subsequent tumor necrosis resulted in a prolonged time to achieve objective tumor regression. In addition, the transient enlargement of the tumor masses may have resulted in premature removal of responding patients. Treatment of eight patients was stopped prior to completion of the planned four treatments due to presumed progression as defined by standard radiographic criteria (>25% increase in tumor size). Functional imaging, such as positron emission tomography (PET) scans, may help distinguish clinical responses from progressive disease following treatment with oncolytic viruses. Onyx-015 may benefit patients with refractory colorectal cancer and additional studies that include PET scans to assess clinical response are warranted.

Topics: Adenoviridae; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Mutation; Neoplasm Metastasis; Treatment Failure; Tumor Suppressor Protein p53; Viral Vaccines

A phase I-II multicenter trial was conducted to define the maximal tolerated dose and describe the activity of an OCFL combination using oxaliplatin (OHP), irinotecan (CPT-11) and 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (CRC).. CRC patients not pretreated with palliative chemotherapy, with performance status < or =1 and adequate haematological, kidney and liver function, were eligible. Treatment consisted in weekly 24-h infusion 5-FU (2300 mg/m(2))/LV (30 mg) and alternating OHP (70-85 mg/m(2), days 1 and 15) and CPT-11 (80-140 mg/m(2), days 8 and 22) repeated every 5 weeks. OHP and CPT-11 were escalated in cohorts of three to six patients.. Thirty patients received a median of five cycles. Dose-limiting toxicity occurred at dose level 3, and the recommended dose was OHP 70 mg/m(2), CPT-11 100 mg/m(2), LV 30 mg and 5-FU 2300 mg/m(2)/24 h. Grade > or =3 toxicities were diarrhea 23%, neutropenia 20%, fatigue 7%, and neurologic 7%. Two febrile neutropenia episodes (one fatal) were recorded. Among 28 patients with measurable disease (90%), we observed two complete and 20 partial responses; overall RR was 78% (95% CI, 59% to 92%). Median time to progression and overall survival were 9.5 and 25.4 months, respectively. Seven patients underwent liver metastases resection.. OCFL is an overall well tolerated regimen with very high efficacy, which makes it most suitable for tumour control before surgery of metastatic disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Prognosis; Survival Analysis; Treatment Outcome

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m(-2) on day 1, FA 200 mg m(-2) as a 2 h infusion followed by bolus 5-FU 400 mg m(-2) and a 22 h infusion of 5-FU 600 mg m(-2), repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Signet Ring Cell; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Stomach Neoplasms; Survival Rate

Pre-clinically, hyaluronan (HA) has been demonstrated to systemically target chemotherapeutic drugs to tumours while ameliorating treatment toxicities. This study is a preliminary clinical investigation to determine if HA could be safely used in combination with 5-fluorouracil (5-FU) and doxorubicin (DOX).. Thirty patients with metastatic cancer were intravenously administered 500 mg/m2 HA in combination with escalating doses of DOX (30-60 mg/m2) or 5-FU (cumulative dose of 1,350-2,250 mg/m2 per cycle). The effect of pre-administration of 20 mg/m2 of folinic acid on HA/5-FU chemotherapy was also investigated. Patients were randomized to receive either HA/chemotherapy or chemotherapy alone in their first treatment cycle and vice versa for the second cycle. Patients received HA and chemotherapy in all subsequent cycles.. Treatment was well tolerated, tumour responses were observed and the co-administration of HA did not alter the pharmacokinetics of clinically relevant doses of 5-FU or DOX.. High doses of intravenous high-molecular-weight HA can be safely co-administered with clinical doses of chemotherapy without significantly altering the toxicity or pharmacokinetics of the drugs or HA.

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Hyaluronic Acid; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasms

In a phase III trial, combining bevacizumab (BV)--a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor--with irinotecan, bolus fluorouracil (FU), and leucovorin (LV; IFL) increased survival compared with IFL alone in first-line treatment of patients with metastatic colorectal cancer (CRC). Results for the parent study of IFL/BV versus IFL/placebo are reported elsewhere. Here, we describe efficacy and safety results for the third patient cohort in this trial, who received BV combined with FU/LV, and compare them with results for concurrently enrolled patients who received IFL.. Patients (N = 923) were randomly assigned to receive IFL/placebo (control), IFL/BV, or FU/LV/BV. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) 5 mg/kg was administered intravenously every 2 weeks. Before an interim analysis confirmed acceptable safety for IFL/BV, 313 patients were concurrently randomly assigned to these three arms; after this analysis, the FU/LV/BV arm was discontinued.. Median overall survivals were 18.3 and 15.1 months with FU/LV/BV (n = 110) and IFL/placebo (n = 100), respectively. Median progression-free survivals were 8.8 and 6.8 months, respectively. Overall response rates were 40.0% and 37.0%, and median response durations were 8.5 and 7.2 months, respectively. Adverse events consistent with those expected from FU/leucovorin- or IFL-based regimens were seen, as were modest increases in hypertension and bleeding in the bevacizumab arm, which were generally easily managed.. The FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile. FU/LV/BV is an active alternative treatment regimen for patients with previously untreated metastatic CRC.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Probability; Prognosis; Risk Assessment; Survival Analysis; Treatment Outcome

Irinotecan combined with continuous-infusion 5-fluorouracil (5FU) has been shown to be an effective and tolerable regimen in the treatment of metastatic colorectal cancer (MCRC). Tegafur/uracil (UFT) during 5FU infusion enhances plasma 5FU concentration, mimics continuous 5FU infusion and delivers the drug to target tumor cells. We conducted a phase II trial of four-agent combined therapy for MCRC, giving patients (pts) intravenous irinotecan (30 mg/m2 on day 1), leucovorin (LV, 200 mg/m2 on day 1 and 2), 5FU (300 mg/m2 on day 1 and 2), and UFT (400 mg/day for 14 days). The main endpoint was the objective tumor response rate. Sixteen pts with a good performance status were enrolled from February 2001 to May 2002. The response rate was 19% (3 partial responses), and 13 pts had stable disease. The median time to progression was 5.2 months, and the median survival time was 20.2 months. Considering the low toxicity and reasonable cost, this regimen deserves further investigation.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Palliative Care; Survival Analysis; Tegafur; Treatment Outcome; Uracil

Seventy-two patients suffering from a metastatic colorectal cancer received, as first line treatment, a combination chronotherapy with 5-FU and folinic acid (infused from 10 pm to 10 am with a peak at 4 am, respectively at doses of 700 and 300 mg/m2 per day) and carboplatin (infused at the dose of 40 mg/m2 per day from 10 am to 10 pm with a peak at 4 pm). The courses of four days were repeated every two weeks. A major tumoral response was observed in 60% cases (68% in those not previously treated with adjuvant chemotherapy). The median times to progression and overall survival established at 11 and 27 months. The clinical (grades 3-4 in maximum 5% cases) and hematological (grades 3-4 in maximum 10-29% cases) toxicities were quite limited. Our observations suggest the interest to incorporate carboplatin in the combined infusional treatment of colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chronobiology Phenomena; Colonic Neoplasms; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Rectal Neoplasms; Survival Analysis

Oxaliplatin plus fluorouracil/folinic acid (5-FU/FA) every 2 weeks has shown promising activity in advanced gastric cancer. This study assessed the efficacy and safety of weekly oxaliplatin plus 5-FU/FA (FUFOX regimen) in the metastatic setting. Patients with previously untreated metastatic gastric cancer received oxaliplatin (50 mg m(-2)) plus FA (500 mg m(-2), 2-h infusion) followed by 5-FU (2000 mg m(-2), 24-h infusion) given on days 1, 8, 15 and 22 of a 5-week cycle. The primary end point of this multicentre phase II study was the response rate according to RECIST criteria. A total of 48 patients were enrolled. Median age was 62 years and all patients had metastatic disease, with a median number of three involved organs. The most common treatment-related grade 3/4 adverse events were diarrhoea (17%), deep vein thrombosis (15%), neutropenia (8%), nausea (6%), febrile neutropenia (4%), fatigue (4%), anaemia (4%), tumour bleeding (4%), emesis (2%), cardiac ischaemia (2%) and pneumonia (2%). Grade 1/2 sensory neuropathy occurred in 67% of patients but there were no episodes of grade 3 neuropathy. Intent-to-treat analysis showed a response rate of 54% (95% CI, 39-69%), including two complete responses. At a median follow-up of 18.1 months (range 11.2-26.2 months), median survival is 11.4 months (95% CI, 8.0-14.9 months) and the median time to progression is 6.5 months (95% CI, 3.9-9.2 months). The weekly FUFOX regimen is well tolerated and shows notable activity as first-line treatment in metastatic gastric cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Stomach Neoplasms; Treatment Outcome

Colorectal cancer is usually diagnosed in elderly patients. Since there is clear evidence that such patients are under-treated and under-represented or even excluded from clinical studies and there are no reliable and prospective data on the feasibility and efficacy of an oxaliplatin (L-OHP)-based chemotherapy in this setting, we have tested the L-OHP plus oral uracil/tegafur (UFT) and oral folinic acid (FA) combination as first-line therapy in patients with advanced or metastatic colorectal cancer (MCRC) aged 70 or older.. Forty-seven patients with advanced or MCRC, aged over 70, were treated with L-OHP 65 mg/m(2) as an intravenous 3-hour infusion on day 1 and 8 plus UFT 300 mg/m(2) and FA 90 mg in 3 divided doses given orally on days 1-14 for each 3-week cycle. Patients were followed by a geriatric and a quality of life (QoL) assessment with specific scales and EORTC-QLQ-C30 questionnaire.. All patients were assessable for toxicity and 45 for response to treatment. Complete response was achieved in 2 patients (4%) and partial response in 22 (47%) [overall response rate, 51%; 95% confidence interval (CI): 40.7-61.2%]; 18 patients (38%) had stable disease, and 5 (11%) had disease progression. The median duration of response was 8 months (range, 3-19+ months). After a minimum follow-up of 17 months, the median time to disease progression and the median overall survival were 8.0 (95% CI: 6.7-9.3%) and 14.1 (95% CI: 11.0-17.1%) months, respectively. Regimen safety was manageable. Most adverse events were mild to moderate, and this did not result in QoL impairment. The most common grade 3-4 treatment-related adverse events were diarrhea (17%), neutro- and thrombocytopenia (2%), laryngeal spasm (2%), and peripheral neuropathy (12.7%). No treatment-related deaths occurred.. These results confirmed that this tested chemotherapy combination is active with acceptable tolerability and QoL maintenance in elderly patients with advanced or MCRC.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Humans; Infusions, Intravenous; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Tegafur; Treatment Outcome; Uracil

The aim of this study was to evaluate the overall response rate, toxicity and overall survival in patients with locally advanced or metastatic esophageal cancer treated with gemcitabine, 5-fluorouracil (5-FU) and leucovorin.. Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus could enroll; however, patients could not have received prior chemotherapy for metastatic disease. Treatment cycles consisted of infusions of all three agents at days 1, 8 and 15, repeated every 28 days. Patients received gemcitabine 1,000, leucovorin 25 and 5-FU 600 mg/m(2). Tumor assessment was performed every 2 cycles. Responses were assessed using the Eastern Cooperative Oncology Group solid tumor response criteria.. Thirty-five patients with metastatic or locally advanced esophageal cancer enrolled. One complete response and ten partial responses were observed for an overall response rate of 31.4%. An additional 11 patients had stable disease as their best response. The median survival was 9.8 months with a 1-year survival rate of 37.1%. Toxicity was predominately hematologic, with 58% of patients experiencing grade 3 or 4 neutropenia.. The combination of gemcitabine, 5-FU and leucovorin had activity in advanced esophageal cancer. Patients tolerated the regimen well, with myelosuppression occurring most commonly. The combination merits further investigation as a treatment for esophageal cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Deoxycytidine; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Treatment Outcome

A biweekly regimen of irinotecan 200 mg/m2 on day 1 and levo-leucovorin (LV) 250 mg/m2 plus 5-fluorouracil (5-FU) 850 mg/m2 via intravenous bolus on day 2 was assessed in 2 consecutive randomized trials in metastatic colorectal cancer (CRC).. Individual data of 254 patients were merged, and baseline features potentially affecting overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and occurrence of severe toxicity were analyzed by univariate and multivariate analyses.. In the pooled series, ORR was 33% (95% confidence interval [CI], 27%-39%). Liver-only disease (47% vs. 25%; P=0.0012) and absence of previous weight loss (38% vs. 20%; P=0.0189) were significantly associated with a higher ORR on the multivariate analysis. Absence of weight loss (hazard ratio, 1.40; 95% CI, 1.02-1.93; P=0.0377) was significantly associated with a longer PFS (7.5 months vs. 6 months). Median OS was 15.1 months (95% CI, 13.5-16.6 months). Primary surgery, good performance status (PS), only one metastatic site, and oxaliplatin-based second-line treatment independently predicted a longer OS. Grade 4 neutropenia was significantly associated with a PS>or=1, whereas risk of grade>or=3 diarrhea was directly related to age and previous weight loss.. Patients with no weight loss and/or preserved PS and with a limited disease extent appeared to obtain the greatest benefit from our irinotecan/5-FU/LV regimen, with acceptable toxicity. Notably, the regimen was effective and well tolerated by elderly patients. This regimen may represent the rationale for assessing the addition of novel antiangiogenic drugs to the treatment of metastatic CRC.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Weight Loss

To evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with bolus and continuous infusion of 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFIRI regimen) as first-line treatment of elderly patients with metastatic colorectal cancer (MCC).. Thirty consecutive, previously untreated patients with metastatic colorectal cancer, aged (median 76 years; range 70-84) were enrolled. The performance status (WHO) was 0 in 8, 1 in 16 and 2 in 6 patients; 19 (63%) patients had prior surgery and 8 (27%) adjuvant chemotherapy. CPT-11 (180 mg/m(2) as a 90 min i.v. infusion) was administered on day 1, LV (200 mg/m(2) as a 2-hour i.v. infusion), 5-FU (400 mg/m(2)/d i.v. bolus followed by 600 mg/m(2)/d as a 22-hour i.v. continuous infusion) were given on days 1 and 2 every 2 weeks.. Complete response was achieved in one (3.3%) patient and partial response in 10 (33.3%) (overall response rate: 36.6%; 95% C.I.: 26.6-48.4%); 11 (36.6%) patients had stable disease and, 8 (26.6%) disease progression. The median duration of response was 7.5 months and the median time to disease progression 7.0 months. After a median follow-up period of 17 months, the median overall survival was 14.5 months. Main toxicities were: grade 3-4 neutropenia (n = 6; 20%), grade 3 thrombocytopenia (n = 1; 3.3%), grade 2 anemia (n = 9; 30%), grade 3-4 diarrhea (n = 5; 17%) and grade 3 asthenia (n = 3; 10%). There was one treatment-related death due to neutropenic sepsis.. The FOLFIRI combination is an active regimen with manageable toxicity as front-line treatment in patients above 70 years of age.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Time Factors; Treatment Outcome

5-fluorouracil (5-FU), irinotecan, and oxaliplatin are the most active drugs in advanced colorectal cancer (CRC), and survival is improved with patient exposure to all of them. The efficacy and safety of an alternating schedule of continuous-infusion 5-FU with leucovorin (LV) plus oxaliplatin (ie, FOLFOX regimen) or irinotecan (ie, FOLFIRI regimen) was assessed in the first-line setting.. Seventy-nine patients with previously untreated, unresectable CRC were included. Treatment consisted of 5-FU/LV (de Gramont schedule) plus oxaliplatin (85 mg/m2) alternated biweekly with the same 5-FU/LV regimen plus irinotecan (180 mg/m2). Treatment was maintained until tumor progression or unacceptable toxicity was noted.. Median age was 62 years. Performance status was 0/1 in 91% of patients, 63% had 1 organ involved, and 80% had liver metastases. A median of 6 courses per patient (range, 1-9) and a total of 952 infusions were given. The most frequent grade 3/4 toxic events were neutropenia (32%), diarrhea (26%), and asthenia (7%). Grade 1/2 neurotoxicity was seen in 59% of cases, but no grade 3/4 neurotoxicity was observed. There were no toxic deaths. An objective response rate of 54% (4 complete responses plus 39 partial responses) was attained. Median time to progression and overall survival were 13 months and 18 months, respectively.. This alternating schedule is active, with efficacy results similar to those seen with sequential protocols, the advantages of less toxicity, and 100% patient exposure to irinotecan and oxaliplatin.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Feasibility Studies; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prospective Studies; Survival Analysis; Treatment Outcome; Vitamin B Complex

A total of 41 metastatic colorectal cancer (CRC) patients received tegafur/uracil (UFT)+leucovorin (LV)+oxaliplatin alternated with UFT/LV+irinotecan. The overall response rate was 58.5% (95% confidence interval, 42.2-73.3%), and the median progression-free survival was 8.8 months. There were no grade 4 toxicities; 12 patients (29%) experienced grade 3 diarrhoea. There were no cases of hand-foot syndrome. This alternating regimen seems to be effective and well tolerated in the first-line treatment of patients with metastatic CRC.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Disease Progression; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Tegafur; Treatment Outcome; Uracil

The purpose of this report is to summarize information on oxaliplatin, a drug recently approved by the U.S. Food and Drug Administration. Information provided includes regulatory history, study design, efficacy and safety results, and pertinent literature references. A single, multicenter, randomized trial, enrolling 463 patients with metastatic colorectal carcinoma whose disease had recurred or progressed during or within 6 months of completion of therapy with the combination of bolus 5-fluorouracil (FU)/leucovorin (LV) and irinotecan, was submitted. Study arms included infusional 5-FU/LV alone (arm A), oxaliplatin alone (arm B), and the combination of oxaliplatin and infusional 5-FU/LV(arm C). Oxaliplatin, at a dose of 85 mg/m2, was administered to patients in arms B and C intravenously over 2 hours in 250-500 ml of dextrose 5% in water (D5W) on day 1 only. A 200-mg/m2 dose of LV was administered simultaneously to arm C patients, in a separate bag using a Y-line, or alone to arm A patients, by i.v. infusion, over 2 hours. 5-FU was then administered to arms A and C patients, first as a bolus injection over 2-4 minutes at a dose of 400 mg/m2, then as a continuous infusion in 500 ml of D5W over 22 hours at a dose of 600 mg/m2. LV was repeated on day 2 of the cycle (arms A and C) followed by a 400-mg/m2 5-FU bolus and a 600-mg/m2 22-hour infusion. Treatment was repeated every 2 weeks. Response rate was the prespecified end point for accelerated approval. Time to progression (TTP) was a secondary end point. The prespecified primary comparison was between the 5-FU/LV regimen and the 5-FU/LV/ oxaliplatin combination regimen. The three arms were well balanced for patient prognostic factors. There were no complete responders. The partial response rates were 0%, 1%, and 9% for the 5-FU/LV, oxaliplatin, and oxaliplatin plus 5-FU/LV treatments, respectively (p = 0.0002, arm C versus arm A). The median times to radiographic tumor progression, based on available radiographs, were 2.7 months, 1.6 months, and 4.6 months, respectively (p < 0.0001, arm C versus arm A). Common adverse events associated with the combination treatment included peripheral neuropathy, fatigue, diarrhea, nausea, vomiting, stomatitis, and abdominal pain. Neutropenia was the major hematologic toxicity. Adverse events were similar in men and women and in patients <65 and > or =65 years of age, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia, and fatigue. Ox

Topics: Antineoplastic Agents; Camptothecin; Colorectal Neoplasms; Disease Progression; Drug Approval; Drug Therapy, Combination; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Random Allocation; Recurrence; United States; United States Food and Drug Administration

This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m(-2) twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.

Topics: Administration, Oral; Adult; Age Factors; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Female; Fluorouracil; Humans; Injections, Intravenous; Karnofsky Performance Status; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Survival Analysis; Treatment Outcome

The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients.. Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combination. Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent.. The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen is warranted.

Topics: Adult; Aged; Amidines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Humans; Indans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pseudomyxoma Peritonei; Rectal Neoplasms; Treatment Outcome

The purpose of this report is to evaluate the efficacy and toxicity (Tx) of a double modulation of 5-fluorouracil (5-FU) by trimetrexate (TMTX) and leucovorin (LV) in patients with advanced recurrent (inoperable) or metastatic colorectal cancer (ACC). Between December 1997 and August 2000, 36 patients were entered in this phase II study. Median age was 61 years, and 18 patients (50%) were female. Median performance status was 0 (range: 0-1), whereas primary tumor location was colon in 21 patients (58%) and rectum in 15 patients (42%). The number of metastatic sites was 1:29 patients (81%); 2:6 patients (17%) and 3:1 patient (3%). Hepatic involvement was observed in 33 patients (92%). Treatment consisted of TMTX 110 mg/m2 IV over 1 hour at hour (H) 0; LV 50 mg/m2 IV over 2 hours IV infusion starting at H 18; and 5-FU 900 mg/m2 IV bolus at H 20. LV (rescue) 15 mg/m2 orally was administered every 6 hours (total 6 doses) beginning at H 24. Cycles were repeated every 2 weeks until progressive disease (PD) or severe Tx. Thirty-four patients are assessable for response (R) (two patients refused further treatment after the first course of therapy), whereas all patients were assessable for Tx. Complete response: 1 patient (3%); partial response: 4 patients (12%), with an overall objective response rate of 15% (95% CI, 1%-25%); no change: 12 patients (35%); and progressive disease: 17 patients (50%). The median time to treatment failure was 4 months and median survival was 11 months. Tx was within acceptable limits. The dose-limiting side effect was mucositis. Eight episodes of grade II or III stomatitis were observed and were responsible for dosage modifications of TMTX and 5-FU. Leukopenia was observed in 16 patients (44%); neutropenia was registered in 19 patients (53%); anemia was seen in 18 patients (50%); emesis in 22 patients (61%); and dermatitis in 3 patients (8%). There were no therapy-related deaths. The double modulation of 5-FU by TMTX and LV showed modest antitumoral activity with mild to moderate Tx.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Survival Analysis; Treatment Failure; Trimetrexate

Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC.. We investigated the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) for CPT-11 given i.v. (90-min infusion) and bolus 5-FU plus biologically active l-LV administered weekly for 3 weeks every 28 days (modified Saltz regimen) in Japanese patients with metastatic CRC. Eighteen patients with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and adequate organ functions were enrolled.. At dose level 2 (CPT-11, 100 mg/m(2); 5-FU, 400 mg/m(2); and l-LV, 25 mg/body), 1 of 6 patients had DLT (febrile neutropenia). At dose level 3 (CPT-11, 100 mg/m(2); 5-FU, 500 mg/m(2); and l-LV, 25 mg/body), 2 of 6 patients had DLT (febrile neutropenia and grade 4 neutropenia lasting more than 4 days). To determine whether level 3 was the MTD level, an additional 3 patients were treated at this level, but no DLT was observed. Consequently, 2 of 9 patients had DLT at level 3, this level thus being considered as the RD. At this level, grade 3-4 neutropenia was common but manageable. Nonhematological toxicities were mild. Seven partial responses were observed in the 18 enrolled patients (response rate [RR], 39%), and 8 patients (44%) experienced stable disease.. This CPT-11/5-FU/ l-LV regimen administered weekly for 3 weeks every 28 days has substantial antitumor activity, with manageable toxicities. A multicenter phase II study is currently underway. Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Folic Acid; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Treatment Outcome

The epothilone B analog, BMS-247550, is a non-taxane microtubulin-stabilizing agent with preclinical activity in taxane-resistant cell lines and phase I activity in colorectal cancer. We conducted a phase II study of single-agent BMS-247550 in advanced colorectal cancer patients who had disease progression following treatment with irinotecan-5-fluorouracil-leucovorin (IFL).. Patients were required to have histologically or cytologically confirmed advanced or metastatic colorectal cancer; progressed on or after chemotherapy with IFL; Eastern Cooperative Oncology Group performance status < or =1; peripheral neuropathy grade < or =1; and adequate laboratory parameters. BMS-247550 40 mg/m(2) was administered intravenously over 3 h every 3 weeks. Patients were evaluated for response every 6 weeks.. Twenty-five patients were enrolled; all were evaluable for toxicity and 23 were evaluable for response. There were no complete or partial responses. Thirteen patients (56%) had stable disease after two cycles of therapy; five patients (20%) received six or more cycles. The median time to progression was 11 weeks; median overall survival was 36 weeks. There was considerable grade 3/4 hematological toxicity, including neutropenia (48%) and leukopenia (36%). Grade 3/4 non-hematological toxicities included grade 3 hypersensitivity reaction (12%) and peripheral neuropathy (20%).. Single-agent BMS-247550 (40 mg/m(2)) administered every 21 days demonstrated no activity in advanced colorectal cancer. Peripheral neuropathy was treatment-limiting.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Disease Progression; Epothilones; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Treatment Failure

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy.. Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life.. The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed.. The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Quality of Life; Survival Analysis

The main objectives of this phase II study were to determine efficacy and safety of the combination of UFT with Leucovorin and mitomycin C in patients with metastatic colorectal cancer. Ninety-seven patients were treated with UFT (91 patients 300 mg/m2, 6 patients 250 mg/m2) + Leucovorin 90 mg days 1-28 q 5 weeks. During the first 4 cycles the patients also received mitomycin C 7 mg/m2 on day 1. At the end of 4 courses patients with benefit from the treatment could receive further courses of UFT and Leucovorin alone. Two patients had a complete response (2%), 20 (21%) had a partial response, 40 (41%) had no change, 19 (20%) had progression, and 16 (17%) were not evaluable for response. The overall response rate by intention to treat was 22/97 (23%). Median time to progression was 5 months and median survival 13 months. Severe (grade 3-4) toxicities included: anorexia 3%, nausea 6%, vomiting 7%, diarrhoea 7%, and fatigue 9%. Febrile neutropenia, renal failure, and thrombocytopenia were seen in 1% of the patients, respectively. The combination of UFT with Leucovorin and mitomycin C shows similar clinical activity with regard to overall response rate (23%) and survival (13 months) to other frontline 5-fluorouracil-based therapies in metastatic colorectal cancer patients. The results indicate that mitomycin C did not increase either efficacy or toxicity. Therefore, phase III trials with this regimen cannot be recommended.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Neoplasm Metastasis; Tegafur; Treatment Outcome; Uracil

FOLFOX, a bimonthly combination of leucovorin, 5-fluorouracil and oxaliplatin, is active in metastatic colorectal cancer, but sometimes causes cumulative sensory neurotoxicity. This retrospective study investigated FOLFOX reintroduction after a break in treatment or following disease progression on another regimen.. FOLFOX was reintroduced in 29 patients. During their previous FOLFOX therapy, 24 had achieved a response, four were stable and one had progression. Median progression-free survival (PFS) was 33 weeks. Grade 3 neuropathy developed in nine and grade 2 neuropathy in eight patients.. Following FOLFOX reintroduction, six patients (21%) showed a response, 15 (52%) were stable and eight (28%) had progression. Median PFS was 18 weeks. Grade 3 neuropathy developed in four patients and grade 2 neuropathy in 11. Two patients with previous grade 3 neuropathy had no recurrence of neuropathy after eight and 18 cycles, respectively. Among 13 patients who received no treatment between periods of FOLFOX therapy, four (31%) had a response and eight (62%) had stable disease.. Reintroduction of oxaliplatin was feasible and achieved a response or stabilization in 73% of patients. These results support the concept of intensified, repeated short courses of FOLFOX, a strategy currently being evaluated prospectively in the OPTIMOX study.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Retrospective Studies

The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced colorectal cancer.. Patients were required to have histologically confirmed colorectal cancer with distant metastases. The treatment regimen consisted of 5-FU 2600 mg/m(2) as a 24-hours continuous infusion given once a week, concurrently with leucovorin (LV) at 500 mg/m(2) as a 24-hour continuous infusion. PALA was administered 24 hours prior to 5-FU/LV at a dose of 250 mg/m(2) iv over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy.. This study accrued 28 patients and all were eligible and evaluable for toxicity. Four patients had inadequate assessment of response and are considered non-responders. There was one complete response and five partial responses for an overall response rate of 6/28 or 21% (95% confidence interval 8-41%). Estimated median survival was 17.4 months (95% confidence interval 13.3-20.5 months). One patient died of a treatment related infection. This patient also had grade 4 diarrhea and vomiting.. The combination of 5-FU, leucovorin, and PALA in the doses and schedule used here, produces a response rate similar to other modulated schedules of 5-FU with similar survival and toxicity profiles.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Phosphonoacetic Acid; Pilot Projects; Survival Rate; Treatment Outcome

The effectiveness of capecitabine, an oral fluoropyrimidine carbamate, is well documented in previously untreated metastatic colorectal cancer patients (overall response rate: 25%). However, its efficacy in patients with metastatic colorectal cancer refractory to 5-fluorouracil/leucovorin (5-FU/LV) has not been determined. This study was performed to evaluate the efficacy and to identify the side-effects of capecitabine in patients with metastatic colorectal cancer showing progression despite 5-FU/LV-based combination chemotherapy.. Fifty-one metastatic colorectal cancer patients who showed progressive disease in 5-FU/LV-containing regimens (median: two regimes) were treated with capecitabine 1,250 mg/m(2) twice daily (days 1-14 repeated every 3 weeks).. Only one partial response was observed (response rate: 2%). Twenty-seven patients (53%) showed stable disease after two cycles. The median time to disease progression of either a partial response or stable disease was 3.4 months. Hand-foot syndrome was the main toxicity of capecitabine and occurred in 35% of cases (grade 3 or 4 in 6%). The median number of cycles administered was two and the relative dose intensity of capecitabine was 80%.. The response rate to capecitabine was low in metastatic colorectal cancers that were refractory to 5-FU/LV-containing chemotherapy. However, disease stabilization was seen in a significant number of patients.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Treatment Outcome

A phase II trial was designed to determine whether mistletoe extract can induce objective tumor response in patients with metastatic colorectal cancer resistant to 5-fluorouracil and leucovorin (5FU/LCV)-based chemotherapy. Twenty-five patients (15 female, 10 male; median age 69 yr) were treated with commercially available mistletoe extract (Abnoba-viscum Quercus) given by three weekly subcutaneous injections with daily dose gradually increased from 0.15 to 15 mg plant extract. Treatment was discontinued if unacceptable toxicity developed or if the patient became bedridden. Median duration of treatment was 14 wk (range, 4-66 wk). Treatment was continued in 14 patients until they became bedridden, and 11 patients decided to discontinue the treatment after their illness progressed. Objective tumor response was not seen in any of the 25 patients (0%, 95% confidence interval 0-13.7%). Stable disease, lasting for a median of 2.5 mo (range, 1.5-7 mo), was noted in 21 (84%) patients. Median survival was 5.5 mo and symptomatic relief was reported by 10 (40%) patients. Toxicity was mild and included mainly local inflammatory reaction. In conclusion, mistletoe extract does not seem to be active in metastatic colorectal cancer resistant to 5FU/LCV in terms of objective tumor response.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Confidence Intervals; Disease Progression; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Fluorouracil; Humans; Injections, Subcutaneous; Karnofsky Performance Status; Leucovorin; Male; Middle Aged; Mistletoe; Neoplasm Metastasis; Phytotherapy; Plant Extracts; Time Factors

A combination of irinotecan 125 mg/m2, 5-fluorouracil (5-FU) 500 mg/m2, and leucovorin (LV) 20 mg/m2 (Saltz regimen; treatment on days 1, 8, 15, and 22 every 6 weeks) is widely used for the treatment of metastatic colorectal cancer. A modified schedule with chemotherapy on days 1 and 8 of a 21-day cycle was recommended in 2001 because of early treatment-related mortality. We conducted a phase I/II study of this modified Saltz regimen as first-line therapy in Japanese patients with metastatic colorectal cancer to assess the maximum tolerated dose (MTD) and the recommended dose of 5-FU when given with fixed doses of l-LV and irinotecan, and to evaluate the efficacy and the feasibility of this regimen.. Irinotecan, 5-FU, and l-LV were administered on days 1 and 8 of a 21-day cycle. Irinotecan 100 mg/m2 was given intravenously over the course of 90 min on day 1, followed by l-LV 10 mg/m2, and then 5-FU. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2). If neither level met the criteria for the MTD, the recommended dose was defined as level 2, and dose escalation was discontinued, because the maximum approved weekly dose of irinotecan alone in Japan is 100 mg/m2 and the dose of 5-FU in the original Saltz regimen was 500 mg/m2.. One patient had grade 4 neutropenia with fever at level 1, and four patients had grade 3 neutropenia at level 2. There was no treatment-related death. Level 2 did not meet the criteria for the MTD. The relative dose intensities of the first five cycles were 91% for both 5-FU and irinotecan at level 1 and 86% for 5-FU and 93% for irinotecan at level 2. The response rates were 58% for all patients, and 69% for patients at level 2. CONCLUSION. Our results confirm that the modified Saltz regimen is safe and efficacious for Japanese patients. The recommended doses for phase II studies are irinotecan 100 mg/m2, 5-FU 500 mg/m2, and l-LV 10 mg/m2.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neutropenia; Treatment Outcome

In a previous phase I-II study we demonstrated that the FOLFOXIRI regimen [irinotecan 125-175 mg/m2 day 1, oxaliplatin 100 mg/m2 day 1, l-leucovorin (l-LV) 200 mg/m2 day 1, 5-fluorouracil (5-FU) 3800 mg/m2 as a 48-h chronomodulated continuous infusion starting on day 1, repeated every 2 weeks] has promising activity and efficacy in metastatic colorectal cancer. However, this regimen required a chronomodulated infusion of 5-FU, and because neutropenia occurred in 32% of cycles, granulocyte colony-stimulating factor (G-CSF) was used and the delivered dose intensity was only approximately 78% of planned. Therefore, we conducted the present phase II study in order to develop a simplified FOLFOXIRI regimen that could be more easily administered in clinical practice as well as in multicenter settings.. A total of 32 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, l-LV 200 mg/m2 day 1 and 5-FU 3200 mg/m2 as a 48-h continuous (not chronomodulated) infusion starting on day 1, repeated every 2 weeks.. All 32 patients were evaluated for safety and the incidence of grade 3-4 toxic effects, and the use of G-CSF seemed to be lower than with the previous FOLFOXIRI regimen: grade 4 neutropenia (34%), grade 3 diarrhea (16%), grade 3 stomatitis (6%) and grade 2-3 peripheral neurotoxicity (37%) were reported, and G-CSF was used in 23% of cycles. Delivered dose intensity was 88% of that planned, and no toxic deaths occurred. The intention-to-treat analysis for activity showed four complete responses, 19 partial responses, seven stable disease and two progressive disease, for an overall response rate of 72% (95% confidence interval 53% to 86%). Eight (25%) patients with residual liver or lung metastases were radically resected after chemotherapy. After a median follow-up of 18.1 months, the median progression-free survival is 10.8 months and median survival is 28.4 months.. This simplified FOLFOXIRI combination can be delivered easily in outpatient settings, with manageable toxic effects, and has very promising antitumor activity. While the safety profile seems to be improved in comparison with our previous FOLFOXIRI regimen, antitumor activity and efficacy appear to be maintained.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

Rothenberg et al called for caution in the palliative use of irinotecan, 5-fluorouracil (5-FU) bolus and leucovorin (IFL schedule), because of early treatment related deaths in C89803 and N9741 studies. The objective of our multicenter phase II study was to evaluate the efficacy and safety of the combination of 5-FU bolus, folinic acid (FA) and irinotecan as first-line chemotherapy for metastatic colorectal cancer. From December 1999 to June 2002 138 patients (pts) were treated. The chemotherapy regimen was as follows: irinotecan 125 mg/m2 i.v. over 90 min and 5-FU 500 mg/m2 preceded by FA 20 mg/m2, both given by bolus, weekly, for 4 weeks every 6 weeks. Treatment continued until disease progression or unacceptable toxicity. Total number of administered cycles was 404. Average dose intensity was 75%. 47 out of 131 evaluable pts achieved a complete (n = 6) or partial (n = 41) response, leading to an overall response rate (RR) of 36% [95% confidence interval (CI) 24% to 48%], stable disease was registered in 50 (38%). The estimated median time to progression and survival were 6.5 months (95% CI 5.2-9.4) and 16.6 months (95% CI 15.1-19.3) respectively. Two-year survival was 35%. Toxicity was well manageable. In 18 (13.8%) pts the chemotherapy was stopped because of toxicity. Treatment related death was not observed. Close clinical monitoring, early recognition of toxicity, immediate therapeutic intervention are recommended for pts receiving IFL. In our experience this regimen has manageable toxicity and appropriate level of dose intensity and seems to be a good option for first-line therapy in metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Israel; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Survival Analysis; Treatment Outcome

Since the need for nonanthracycline-containing chemotherapy regimens increases with the increased use of anthracyclines in earlier stages of breast cancer, we investigated the feasibility of the combination of docetaxel and 5-fluorouracil (5-FU) with folinic acid (FA).. Anthracycline-pretreated patients with metastatic breast cancer were eligible. Docetaxel was administered as a one-hour infusion every three weeks on day 1, FA 500 mg/m2 (fixed dose) as a two-hour infusion on days 1 and 15 and 5-FU as a 24-hour infusion on days 1 and 15. The dose levels tested were (docetaxel/5FU in mg/m2): 60/1800, 75/1800, 85/1800, 100/1800, and 100/2100.. Altogether 28 patients were accrued and treated in this multicentre open-label study. Dose-limiting toxicities (DLTs) were not observed at dose level I, and in two patients in each of the higher dose levels. DLTs observed were grade III/IV infection (n=4), febrile neutropenia (n=2), diarrhoea (n=1) and erythema (n=1). Partial responses were observed in 10 out of 24 evaluable patients (42%, 95% confidence interval 22.1 to 63.4%). Dose escalation beyond the highest dose level (100/2100) was deemed inappropriate, because these dose levels correspond to recommended dose levels for each drug as a single agent.. Combination of docetaxel (100 mg/m2, one-hour infusion q3 weeks on day 1), FA (500 mg/m2, two-hour infusion on days 1 and 15) and 5-FU (2100 mg/m2, 24-hour infusion on days 1 and 15) is a feasible regimen with encouraging activity in anthracycline-pretreated patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Taxoids

This phase II study was designed to evaluate the efficacy and toxicities of oral doxifluridine plus leucovorin as a randomized trial with those of intravenous 5-fluorouracil (5-FU) plus leucovorin in previously untreated metastatic colorectal cancer (CRC). Patients with metastatic CRC were randomized in either group A (oral doxifluridine 1,000 mg/m /d plus leucovorin 30 mg/d on days 1 to 7 and 15 to 21 of each cycle), or group B (intravenous 5-FU 400 mg/m /d plus leucovorin 20 mg/m /d on days 1-5 of each cycle), with the cycles repeated every 4 weeks. Between July 1998 and May 2000, 77 patients were enrolled (38 in group A and 39 in group B). Response rates were 23.7% (95% CI, 11-42%) in group A, and 15.4% (95% CI, 0-25%) in group B on an intent-to-treat analysis. The median response durations of the two groups were similar with 5.6 months in group A and 5.5 months in group B. Progression-free survival and overall survival were 5.4 months and 14.9 months in group A; 4.7 months and 19.5 months in group B. Toxicities in both groups were generally mild and reversible. This study shows that a combination of oral doxifluridine plus leucovorin can be active and safe as a first-line treatment for patients with metastatic CRC.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Floxuridine; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis

This phase II multicenter trial evaluated the efficacy and toxicity of weekly paclitaxel, 5-fluorouracil, and leucovorin administered as first-line therapy for metastatic breast cancer.. The study enrolled 155 women with pathologically confirmed and measurable metastatic adenocarcinoma of the breast. Treatment consisted of paclitaxel 80 mg/m2, 5-fluorouracil 425 mg/m2, and leucovorin 20 mg/m2 administered weekly 4 x per 4-week cycle in the first 40 patients enrolled (group 1), and weekly 3 x per 4-week cycle in the subsequent 115 patients (group 2) enrolled. Hematologic growth factor support was not routinely used. Twenty patients with hepatic dysfunction were enrolled to assess the tolerability of the regimen in this population. All therapies were delivered in an outpatient setting.. The overall response rate was 48%, with 12-month estimated survival rates of 53% and 65% for treatment groups 1 and 2, respectively. Response rates were not statistically different between the two treatment schedules. Therapy was well tolerated when delivered on the every 3 of 4-week schedule, including patients with hepatic involvement and those age > or = 65.. Weekly therapy with paclitaxel and 5-fluorouracil with leucovorin is active as first-line therapy for metastatic breast cancer. Use of this regimen should be given consideration, particularly in patients who are not candidates for anthracycline-based therapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Remission Induction; Survival Analysis; Treatment Outcome

To determine whether biochemical modulation with LV (leucovorin) enhances the efficacy of CAF (cyclophosphamide, doxorubicin, and fluorouracil) against metastatic breast cancer.. Women with histologically confirmed stage IV breast cancer, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, and no prior chemotherapy for metastatic disease were randomly assigned to receive CAF (cyclophosphamide 500 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, and fluorouracil [FU] 200 mg/m2 intravenous bolus days 1 to 5) with or without LV (LV 200 mg/m2 over 30 minutes days 1 to 5 given 1 hour before FU).. Two hundred forty-two patients were randomly assigned to treatment; 124 patients had visceral crisis and 40 patients had a CALGB performance status score of 2. The median follow-up was 6 years. The two study arms were similar with regard to serious adverse events; four patients died from treatment-related causes, two patients on each study arm. Predictive variables for time to treatment failure and survival were visceral disease and performance status. The overall response rate was 29% for CAF versus 28% for CAF plus LV. The median time to treatment failure (9 months) and median survival (1.7 years) did not differ by treatment arm.. Modulation of CAF with LV improved neither response rates nor survival among women with metastatic breast cancer, compared with CAF alone. Multivariate analyses confirmed the prognostic importance of performance status and visceral crisis. However, the overall and complete response rates, response durations, time to treatment failure, and survival were the same in the two treatment arms.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Disease Progression; Doxorubicin; Female; Fluorouracil; Health Status; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Prognosis; Survival; Treatment Outcome; Viscera

Preclinical and clinical models have demonstrated that cyclooxygenase-2 (COX-2) is overexpressed in primary and metastatic colorectal tumors. In preclinical models, there appears to be additive or synergistic effects when combining 5-Fluorouracil (5-FU) with nonsteroidal anti-inflammatory agents (NSAIDs) for the treatment of colorectal neoplasms. This data raised the question as to whether adding a COX-2 inhibitor to 5-FU-based regimens would increase the response rates with an acceptable toxicity profile in patients with metastatic colon cancer. In the current study, patients with metastatic colorectal cancer, who were either untreated or previously treated (more than 1 year ago) with adjuvant 5-FU and Leucovorin (LV) received 5-FU and LV (Mayo regimen) in addition to Rofecoxib. Tumor samples from all patients exhibited evidence of moderate COX-2 over-expression. 4 patients entered on the study developed upper gastrointestinal bleeding (grade III). Other toxicities included grade II stomatitis (3 patients), grade II thrombocytopenia (1 patient), grade II diarrhea (2 patients) and grade I nausea (1 patient). There were no partial or complete responses in the first 10 patients entered on the study so the study was terminated (probability of success < 0.3 with type 1 error of 0.05 and power of 0.8). Thus, Rofecoxib did not appear to increase antitumor activity and resulted in increased gastrointestinal toxicity when combined with 5-FU/LV. Future studies will need to consider the added gastrointestinal toxicity of Rofecoxib when combined with chemotherapy for the treatment of patients with colorectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Female; Fluorouracil; Humans; Isoenzymes; Lactones; Leucovorin; Male; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Prostaglandin-Endoperoxide Synthases; Sulfones

The pharmacokinetics of ftorafur, 5-fluorouracil (5FU) and uracil were investigated in order to built a population pharmacokinetic model for the anticancer drug UFT, administered with leucovorin and vinorelbine.. A total of 31 patients with metastatic breast cancer were treated with escalating oral doses of UFT (300 to 500 mg per day) plus leucovorin (90 mg per day) in combination with intravenous vinorelbine (15 to 25 mg/m(2)). Concentration-time data were obtained on days 1, 8, 15 and 21 of cycle 1.. Of the 31 patients treated, 30 were available for the pharmacokinetic analysis. Ftorafur, 5FU and uracil appeared rapidly in plasma and showed large interpatient variations. Ftorafur concentrations were higher than those of 5FU and uracil. AUC significantly increased between day 1, and days 8, 15 and 21. Ftorafur C(max) and AUC values were proportional to UFT dose, whereas C(max) and AUC values of 5FU and uracil were not linearly related to UFT dose. The pharmacokinetics of ftorafur were ascribed to a two-compartment open model in which 5FU was produced from the central compartment. The absorption and exponential distribution rate constants were assumed equal. The effect of uracil on 5FU elimination was straightforward, since no reasonable curve-fitting could be obtained for 5FU data when this covariate was not taken into account. The uracil concentration inducing a 50% reduction in 5FU elimination was 2.67 micro mol.l(-1). This result confirms the important role played by uracil as a competitive inhibitor of 5FU catabolism.. A pharmacokinetic model for ftorafur and 5FU was developed and should be useful to further study drug interactions and establish dosing guidelines.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Models, Biological; Neoplasm Metastasis; Tegafur; Uracil; Vinblastine; Vinorelbine

In North America, no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan, bolus fluorouracil (FU), and leucovorin (IFL).. Patients with metastatic colorectal cancer who progressed after IFL therapy were randomly assigned to bolus and infusional FU and leucovorin (LV5FU2), single-agent oxaliplatin, or the combination (FOLFOX4). This planned interim analysis evaluated objective response rate (RR), time to tumor progression (TTP), and alleviation of tumor-related symptoms (TRS) in an initial cohort of patients.. Between November 2000 and September 2001, 463 patients from 120 sites in North America were randomly assigned to treatment. FOLFOX4 proved superior to LV5FU2 in all measures of clinical efficacy. Objective RRs determined by an independent radiology panel were 9.9% for FOLFOX4 versus 0% for LV5FU2 (Fisher's exact test, P <.0001). Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 (two-sided, stratified log-rank test, P <.0001). Relief of TRS occurred in 33% of patients treated with FOLFOX4 versus 12% of patients treated with LVFU2 (chi2 test, P <.001). Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy. Patients treated with FOLFOX4 experienced a higher incidence of clinically significant toxicities than patients treated with LV5FU2, but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate.. For patients with metastatic colorectal cancer, second-line treatment with FOLFOX4 is superior to treatment with LVFU2 in terms of RR, TTP, and relief of TRS.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate; United States

Irinotecan has shown activity in advanced colorectal cancer resistant to leucovorin and fluorouracil. Preclinical experiments on cell cultures and human tumor xenografts indicated potential synergy when combining irinotecan and fluorouracil. We designed a new regimen combining leucovorin, fluorouracil, irinotecan, and hydroxyurea (FOLFIRI-2) and conducted a phase II study to establish its efficacy and tolerance in advanced colorectal cancer refractory to fluorouracil and oxaliplatin. Treatment was repeated every 2 weeks and consisted of leucovorin 400 mg/m2 on day 1, immediately followed by 46 hours of continuous infusion of fluorouracil 2,000 mg/m2, irinotecan 180 mg/m2 on day 3, and hydroxyurea 1,500 mg the day before leucovorin, and on days 1 and 2. Treatment was continued until progression or limiting toxicity. Twenty-nine heavily pretreated patients entered the study. Five patients achieved an objective response (17%), and 12 obtained stabilization of disease or minor response (52%). Five patients failed to continue treatment (17%) because of toxicity or worsening condition. From the start of FOLFIRI-2 treatment, median progression-free survival was 4.1 months and median survival was 9.7 months. Grade III/IV National Cancer Institute-Common Toxicity Criteria toxicities were nausea 17%, diarrhea 31%, mucositis 14%, neutropenia 52%, and febrile neutropenia 14%. FOLFIRI-2 achieved a good rate of response and stabilization in heavily pretreated patients despite significant toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Hydroxyurea; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis

In this multicenter phase II study the efficacy and safety of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) were assessed as first-line chemotherapy in patients with metastatic colorectal cancer (CRC).. Enrolled in the study were 43 patients with advanced CRC. They received CPT-11 350 mg/m2 i.v. on day 1, alternating with LV 20 mg/m2 i.v. and 5-FU 425 mg/m2 i.v. daily for five consecutive days, on days 22-26 (Mayo Clinic regimen). One cycle consisted of 6 weeks.. A total of 179 cycles were administered with a median of four per patient (range one to nine). Efficacy was analyzed on an intention-to-treat basis. The overall objective response rate was 30% (95% CI 16-44), with four complete responses and nine partial responses, whereas 20 patients (4%) showed stable disease. The median time to disease progression was 9.0 months and median survival was 18.5 months. Grade 3/4 diarrhea was mainly related to CPT-11 rather than to 5-FU (9.3% vs 4.7% of patients), whereas grade 3/4 neutropenia was higher during 5-FU administration (16.3% vs 7.0% of patients).. The alternating schedule of CPT-11 with 5 days bolus of 5-FU and low-dose LV showed a clinical benefit in terms of tumor growth control as first-line treatment of patients with metastatic CRC. The overall safety data confirmed this alternating combination as a well-tolerated treatment.

Topics: Adolescent; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis

To determine the activity of biweekly oxaliplatin, combined with weekly bolus fluorouracil (FU) and low-dose leucovorin (LV) chemotherapy (bFOL), as first-line therapy for patients with metastatic colorectal cancer.. Patients with measurable metastatic colorectal cancer; no previous therapy for advanced disease (adjuvant therapy allowed if >6 months since completion); and performance status 0, 1, or 2 were eligible and were treated with oxaliplatin 85 mg/m2 days 1 and 15 plus LV 20 mg/m2 over 10 to 20 minutes, followed by a 500 mg/m2 bolus dose of FU on days 1, 8, and 15 every 28 days. Patients underwent response evaluation by computed tomographic scan every 2 months.. Forty-two patients were entered, and 41 patients were treated, including 20 men and 22 women, nine with previous adjuvant chemotherapy and four with radiation therapy. Three patients achieved complete response, and 23 patients achieved partial response, for a response rate of 63% (95% CI, 49% to 78%). Major toxicities included cumulative neuropathy grade 2 (24%) and grade 3 (12%; requiring discontinuation of oxaliplatin), diarrhea grade 3 to 4 (29%) and grade 3 to 4 hematologic toxicity (10%). Median time to progression was 9.0 months (95% confidence interval, 7.1 to 10.8 months) with median survival of 15.9 months (95% confidence interval, 11.4 to 19.7 months).. The bFOL regimen seems to have activity comparable to be infusional programs of FU combined with oxaliplatin. Prospective trials are warranted to determine the relative merits of this schedule compared with the currently indicated schedules.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Confidence Intervals; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Probability; Remission Induction; Risk Assessment; Survival Rate; Treatment Outcome

This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV.. A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m2 intravenously + LV 20 mg/m2 on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + LV)-all given weekly x6 followed by a 2-week rest period. Survival was the major study end point.. With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P =.724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P =.029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms.. Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Quality of Life; Survival Rate; Treatment Outcome

To evaluate the efficacy and safety of irinotecan as second-line treatment in patients with advanced colorectal cancer (ACC) failing or relapsing after 5-fluorouracil (5-FU) plus leucovorin (LV) standard chemotherapy.. Irinotecan was randomly administered in two different schedules (once every 3 weeks, and every 10 days) in patients failing prior 5-FU plus LV. Patients were randomized to two treatment groups: group A received irinotecan 350 mg/m2 every 21 days and group B received irinotecan 175 mg/m2 days 1 and 10 every 21 days.. Group A comprised 60 patients: 34 male/26 female, median age 64 years (range 48-70 years), and median Karnofsky performance status (PS) 90. Their metastatic sites included liver (n=47), lymph nodes (n=27), lung (n=14), abdomen (n=14), pelvis (n=8), "other" (n=2), and local recurrence (n=12). Group B comprised 60 patients: 36 male/24 female, median age 62 years (46-70 years), and median PS 90. Their metastatic sites included liver (n=49), lymph nodes (n=29), lung (n=17), abdomen (n=16), pelvis (n=11), "other" (n=2), and local recurrence (n=13). Group A showed the following responses: complete response (CR) 2, partial response (PR) 12, stable disease (SD) 21, progressive disease (PD) 26, overall response rate (ORR) 23%, tumor growth control 58%. Group B showed the following responses: CR 1, PR 14, SD 22, PD 23; ORR 25%; tumor growth control 62%. Toxicities included acute cholinergic syndrome (group A 53%, group B 19%; P<0.0001), late-onset diarrhea grade 1/2 (group A 21%, group B 46%) and grade 3/4 (group A 41%, group B 66%; P<0.0001), nausea and vomiting grade 1/2 (group A 34%, group B 59%) and grade 3/4 (group A 30%, group B 12%; P<0.0001), neutropenia grade 3/4 (group A 27%, group B 28%; P<0.03), with febrile neutropenia seen in only four patients in group A, anemia grade more than 2 (group A 28%, group B 12%; P<0.05), asthenia grade more than 3 (group A 24%, group B 18%; P<0.001), and alopecia grade more than 3 (group A 40%, group B 34%; P<0.2).. . The present study indicates that, in patients with ACC who have relapsed after 5-FU plus LV, the administration of irinotecan fractionated into two doses every 21 days yields a similar efficacy to, but a much lower incidence of toxicity than, the same total dose of irinotecan administered once every 21 days.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Karnofsky Performance Status; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Rectal Neoplasms; Topoisomerase I Inhibitors

Phase II studies have suggested an improved response rate and acceptable toxicity profile associated with gemcitabine combinations compared to gemcitabine alone for treatment of metastatic adenocarcinoma of the pancreas. The GFP regimen (gemcitabine, 5-fluorouracil, leucovorin, and cisplatin) is based on laboratory evidence of disease-specific chemotherapy interaction. This retrospective analysis examined the outcome of 49 consecutive patients with histologically confirmed metastatic pancreatic adenocarcinoma treated between July 1998 and September 2000. Day 1 treatment consisted of gemcitabine 500 mg/m2 over 30 minutes and then leucovorin 300 mg bolus, 5-fluorouracil (5-FU) 400 mg/m2 bolus, followed by infusional 5-FU 600 mg/m2 over 8 hours. Day 2 consisted of leucovorin 300 mg bolus, 5-FU 400 mg/m2 bolus, followed by cisplatin 50-75 mg/m2 over 30 minutes and then infusional 5-FU 600 mg/m2 over 8 hours. Treatment was administered every 2 weeks. Median patient age was 61.5 years, 74% were men, and 20 patients had refractory disease (11 patients had disease progression upon gemcitabine-based therapy). Grade 3-4 toxic effects (% patients) consisted of neutropenia (30%), thrombocytopenia (14%), anemia (8%), and neutropenic fever (2%). Grade 3-4 nonhematological toxicities (% patients) consisted of neuropathy (14%), ototoxicity (8%), nephrotoxicity (6%), nausea/vomiting (14%), and mucositis (10%). The majority of dose reductions were made for neuropathy or cytopenias. Filgrastim and erythropoietin were given as needed to promote dose intensity. Eight patients attained a partial response (PR) by RECIST criteria. Fourteen had stable disease (SD). Two patients attaining PR and two attaining SD had progressive disease with prior gemcitabine-based therapy. The median time to disease progression (TTP) from GFP start was 9 weeks. For all 49 patients, the median overall survival (OS) from GFP start was 10.6 months, 12-month survival was 46%, and 24-month survival was 30%. Notably, upon disease progression, 31 patients continued to receive the GFP regimen with irinotecan 80 mg/m2 inserted on day 1 following gemcitabine, the G-FLIP regimen (gemcitabine, 5-fluorouracil, leucovorin, irinotecan, and cisplatin). Measured from G-FLIP initiation, the TTP for the 31 patients treated sequentially was 10 weeks, and for the 14 patients attaining SD or PR the TTP was 25 weeks. The median overall survival measured from GFP initiation was 11.8 months. The response rate, non-cross r

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome

To evaluate the toxicity and efficacy of a modified deGramont regimen of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin in patients with advanced colorectal cancer who have progressed on at least one but not more than two prior chemotherapy regimens.. Patients with stage 4 colorectal cancer were treated with oxaliplatin 85 mg/m2 by a 2-hour intravenous infusion, followed by leucovorin 500 mg/m2 by a 2-hour intravenous infusion, followed by 5-FU 400 mg/m2 by bolus injection, followed by 5-FU 2.4 g/m2 administered by a 46-hour continuous infusion. Cycles were administered every 2 weeks.. Seventy patients were treated and 68 patients had previously received irinotecan. Eleven percent of patients had a partial response, 33% of CEA-evaluable patients had a > or = 50% drop in their CEA level. The median time to progression was 6.2 months, and the median overall survival was 8.7 months. Toxicity was mild to moderate, as 14% of patients experienced grade 3 or 4 neutropenia and 3% of patients experienced grade 3 neuropathy.. The modified deGramont regimen of 5-FU, leucovorin, and oxaliplatin is tolerable and is associated with a modest degree of antitumor activity in patients who have progressed on both 5-FU and irinotecan.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; Treatment Outcome

The tolerance and efficacy of oxaliplatin and irinotecan for metastatic colorectal cancer are unknown in elderly patients. Methods. All consecutive patients over 74 years treated with oxaliplatin or irinotecan for metastatic colorectal cancer were enrolled. The tumour response was assessed every 2-3 months and toxicity was collected at each cycle according to World Health Organisation criteria. A total of 66 patients were enrolled from 12 centres. The median age was 78 years (range, 75-88 years); 39 patients had no severe comorbidity according to the Charlson score. In total, 44 and 22 patients received oxaliplatin or irinotecan, respectively, in combination with 5-fluororuracil+/-folinic acid or raltitrexed in 64 patients. A total of 545 chemotherapy cycles were administered in first (41%), second (51%) or third line (8%). A dose reduction occurred in 190 cycles (35%). Complete response, partial response and stabilisation occurred in 1.5, 20 and 47% of patients, respectively. The median time to progression and overall survival were 6.8 and 11.2 months in first line and 6.3 and 11.6 months in second line, respectively. Grade 3 and 4 toxicity occurred in 42% of patients: neutropenia 17%, diarrhoea 15%, neuropathy 11%, nausea and vomiting 8% and thrombopenia 6%. There was no treatment-related death. In selected elderly patients, chemotherapy with oxaliplatin or irinotecan is feasible with manageable toxicity.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Survival Analysis; Thiophenes; Treatment Outcome

Oral capecitabine achieves a superior response rate with an improved safety profile compared with bolus 5-fluorouracil-leucovorin (5-FU/LV) as first-line treatment for patients with metastatic colorectal cancer. We report here the results of a large phase III trial investigating adjuvant oral capecitabine compared with 5-FU/LV (Mayo Clinic regimen) in Dukes' C colon cancer.. Patients aged 18-75 years with resected Dukes' C colon carcinoma were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily, days 1-14 every 21 days (n = 993), or i.v. bolus 5-FU 425 mg/m(2) with i.v. leucovorin 20 mg/m(2) on days 1-5, repeated every 28 days (n = 974).. Patients receiving capecitabine experienced significantly (P <0.001) less diarrhea, stomatitis, nausea/vomiting, alopecia and neutropenia, but more hand-foot syndrome than those receiving 5-FU/LV. Fewer patients receiving capecitabine experienced grade 3 or 4 neutropenia, febrile neutropenia/sepsis and stomatitis (P <0.001), although more experienced grade 3 hand-foot syndrome than those treated with 5-FU/LV (P <0.001). Capecitabine demonstrates a similar, favorable safety profile in patients aged <65 years or > or = 65 years old.. Based on its improved safety profile, capecitabine has the potential to replace 5-FU/LV as standard adjuvant treatment for patients with colon cancer. Efficacy results are expected to be available in Keywords: Adjuvant treatment, capecitabine, chemotherapy, colorectal cancer

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Safety

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Italy; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

This study combined oxaliplatin with the Nordic bolus schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. Twenty-seven patients were treated every second week with oxaliplatin 85 mg/m2 as a 2-h infusion on day 1, followed by a 3-min bolus injection with 5-FU 500 mg/m2 and 30 min later a bolus injection with FA 60 mg/m2 given on days 1 and 2. Seventeen patients achieved a complete (n = 2) or partial (n = 15) response, leading to a confirmed response rate of 63% (95% CI 45-81%). The estimated median times to progression and survival were 8.9 and 18.7 months, respectively. Neutropenia grade 3-4 toxicity was seen in 63% of patients, neuropathy grade 3 in one patient and grade 2 in 12 patients. Oxaliplatin combined with the bolus Nordic schedule of 5-FU/ FA (Nordic FLOX) appears to be well tolerated, effective and feasible as first-line treatment of metastatic colorectal cancer yielding results comparable with those obtained by more complex schedules.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Analysis

Raltitrexed (Tomudex) is proven effective in metastatic colorectal cancer. Between 1998-2000, 25 patients were included in a randomized phase II study comparing raltitrexed (13 patients) and the Nordic FLv regimen (12 patients). 23 patients were evaluable for response. The overall response rate was 2/12 (1 CR, 1 PR) in the raltitrexed arm and 1/11 (1 CR) in the Nordic FLv arm, respectively. There was no difference in overall survival (raltitrexed--14.7 months, Nordic FLv--15.4 months). 23 patients were evaluable for Quality of Life (QoL) analysis. 23/25 and 17/21 questionnaires (EORTC QLQ C-30) were returned at baseline and first evaluation. Raltitrexed tended to be the most toxic regimen, when looking at nausea and vomiting, appetite loss, diarrhea and global QoL. However, most patients (65%) recommended the raltitrexed treatment schedule. The total treatment cost was equal in both arms (about 6,800 EURO/patient) and the hospital/hospital hotel stay costs accounted for more than half of it.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Health Care Costs; Humans; Length of Stay; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Norway; Quality of Life; Quinazolines; Surveys and Questionnaires; Survival Analysis; Thiophenes; Treatment Outcome

Second- and third-line treatments remain a challenge in advanced colorectal cancer. Studies of bimonthly regimens of high-dose leucovorin (LV) and 5-fluorouracil (5-FU) by continuous infusion combined with oxaliplatin (L-OHP) have shown encouraging response rates in patients not responding to a bimonthly LV/5-FU regimen. Hyperthermic enhancement of L-OHP efficiency by increased DNA adduct formation has been demonstrated in vitro. This study was designed to address feasibility, toxicity and efficacy issues of whole-body hyperthermia (WBH) as an adjunct to L-OHP/LV/5-FU in pretreated patients after progression to first- and second-line treatments with LV/5-FU by continuous infusion and irinotecan.. Forty-four patients with advanced colorectal cancer, who had progressed during or within 3 months after completion of chemotherapy with LV/5-FU 24-h infusion (LV/5-FU(24h)) (eight patients) or irinotecan combined with or after LV/5-FU(24h )(36 patients), were treated with L-OHP 85 mg/m(2), 2-h intravenous (i.v.) infusion, followed by LV 200 mg/m(2), 1-h i.v. infusion, and 5-FU 3 g/m(2), 48-h continuous infusion. Every second cycle of the biweekly regimen was combined with WBH, thus allowing a comparison of toxicity with and without WBH in the same patient. Whole-body hyperthermia was administered by a humidified radiant heat device. The target temperature of 41.8 degrees C was maintained for 60 min. L-OHP (2-h infusion) was started at a core body temperature of 39 degrees C.. All patients could be evaluated for toxicity, and 41 patients were evaluable for response. A total of 273 L-OHP-containing regimens were administered, 130 with and 143 without WBH. Hyperthermic treatment combined with L-OHP/LV/5-FU showed no unexpected toxicities. WHO grade 3 toxicities were rare and evenly balanced between cycles given with or without WBH. One early death occurred due to sepsis and tumor lysis. The overall response rate was 20%, with two complete and six partial responses. Twenty-three patients (56%) had stable disease and nine patients (22%) progressive disease. With a median observation time of 70 weeks, the median time to progression was 21 weeks [95% confidence interval (CI) 17-25 weeks] and the median survival was 50 weeks (95% CI 39-61 weeks) from the start of therapy.. This trial suggests some advantage of combining L-OHP/LV/5-FU with WBH. Results compare favorably with the activity of similar regimens without WBH in less extensively pretreated patients. These data support further evaluation and warrant phase III studies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hyperthermia, Induced; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

This phase III study was designed to demonstrate equivalence in survival of oral uracil/tegafur (UFT) and oral leucovorin (LV) to conventional intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma. Safety was also compared.. Eight hundred sixteen patients were randomized to receive either UFT (300 mg/m(2)/d) and LV (75 or 90 mg/d) for 28 days every 35 days or IV bolus 5-FU (425 mg/m(2)/d) and LV (20 mg/m(2)/d) for 5 days every 28 days.. UFT/LV produced survival comparable to the IV 5-FU/LV regimen. Median survival was 12.4 months (95% confidence interval [CI], 11.2 to 13.6 months) with UFT/LV and 13.4 months (95% CI, 11.6 to 15.4 months) with 5-FU/LV (P =.630). The hazard ratio for survival was 0.964 (95.6% CI, 0.826 to 1.125), supporting equivalent survival. The overall response rate did not differ between treatment arms (UFT/LV, 11.7%; 5-FU/LV, 14.5%; P =.232). Median time to progression favored 5-FU/LV (UFT/LV, 3.5 months; 5-FU/LV, 3.8 months; P =.011), but tumor assessment schedules differed between arms. UFT/LV significantly improved safety compared with 5-FU/LV. Diarrhea, nausea and vomiting, and stomatitis and mucositis were significantly less frequent with UFT/LV, as was myelosuppression. Patients treated with UFT/LV had fewer episodes of febrile neutropenia (P <.001) and documented infections (P <.05). Increased bilirubin, without other liver function abnormalities, was observed more often with UFT/LV (P <.001). Concomitant medications were more frequent with 5-FU/LV, including use of antibiotics, growth factors, and antiemetics.. UFT/LV provided a safer, more convenient oral alternative to a standard bolus IV 5-FU/LV regimen for metastatic colorectal cancer while producing equivalent survival.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Quality of Life; Survival Rate; Tegafur; United States; Uracil

This phase III study compared the time to progression (TTP) of an oral regimen of dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine composed of a fixed combination of tegafur and uracil in a 1:4 molar ratio (UFT) and leucovorin (LV) to intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma (CRC) patients. Secondary end points were survival, tumor response, safety, and quality of life.. Between May 1996 and July 1997, 380 patients were randomized to receive either UFT (300 mg/m(2)/d) and LV (90 mg/d), administered for 28 days every 35 days, or 5-FU (425 mg/m(2)/d) and LV (20 mg/m(2)/d), given IV for 5 days every 35 days.. No statistically significant difference in TTP was observed between treatments. With 320 events assessed, the median TTP was 3.4 months (95% Confidence interval [CI], 2.6 to 3.8) on UFT/LV and 3.3 months (95% CI, 2.5 to 3.7) on 5-FU/LV (P =.591, stratified log-rank test). There were no statistically significant differences in survival, tumor response, duration of response, and time to response. Substantial safety benefits were observed in patients treated with UFT/LV. They experienced significantly less stomatitis/mucositis (P <.001) and myelosuppression, resulting in fewer episodes of febrile neutropenia (P <.001) and less documented infection (P =.04). Concomitant medication usage was significantly greater on 5-FU/LV (P =.010). With respect to quality of life, after correcting for baseline imbalances, there were no significant differences between treatments for any scale, except diarrhea.. The oral UFT/LV regimen failed to achieve improved TTP; however, the study confirms significant safety improvements compared with bolus IV 5-FU/LV for the first-line treatment of metastatic CRC.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Europe; Female; Fluorouracil; Humans; Infusions, Parenteral; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Quality of Life; Survival Rate; Tegafur; Uracil

We studied the activity of combined oxaliplatin and fluorouracil-leucovorin in 16 consecutive patients with advanced biliary tract adenocarcinomas. The disease control rate (responses and stable disease) was 56% (95% confidence interval, 29-84%) and the median overall survival time was 9.5 months (range 0.9-26.8+). Therefore, this regimen might be active in biliary adenocarcinomas with further evaluation necessary.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Treatment Outcome

To determine the feasibility, recommended doses, plasma pharmacokinetics, and antitumor activity of a biweekly chemotherapy regimen with oxaliplatin (L-OHP), irinotecan (CPT-11), infusional fluorouracil (5-FU), and leucovorin (LV) in metastatic colorectal cancer patients.. Patients received CPT-11 followed by L-OHP and LV 200 mg/m(2) and followed by 5-FU 3,800 mg/m(2) as a 48-hour infusion, repeated every 2 weeks. In the first part of the study, an escalation of CPT-11 dose and/or a decrease of the L-OHP dose were planned. Once the recommended doses of CPT-11 and L-OHP were determined, all subsequent patients were treated at the recommended doses.. Forty-two patients entered the study. CPT-11 175 mg/m(2) and L-OHP 100 mg/m(2) in combination with LV 200 mg/m(2) and 5-FU 3,800 mg/m(2) could be administered with acceptable toxicities; 39 patients were treated at these dose levels. The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhea and neutropenia, with 14% of patients experiencing one episode of febrile neutropenia. In five patients (11.9%) a complete and in 25 (59.5%) a partial response was demonstrated, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). In 11 patients (26%), a surgical resection of residual disease could be performed. Median progression-free and overall survival times were 10.4 and 26.5 months, respectively.. This biweekly regimen is feasible and has acceptable and manageable toxicities and no apparent relevant pharmacokinetics interactions. This combination is associated with a promising antitumor activity, time to progression, and survival. A phase III randomized trial in Italy planned by the Gruppo Oncologico Nord Ovest has just started.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pilot Projects; Survival Analysis; Treatment Outcome

To assess the activity and safety of combined folinic acid (FA), 5-fluorouracil (5-FU) and mitomycin C (MMC) in metastatic breast cancer patients previously treated with at least two chemotherapy regimens.. A total of 104 consecutive patients were enrolled for treatment with FA 100 mg/m(2) plus 5-FU 400 mg/m(2) i.v. on days 1-5, and MMC 3 mg/m(2) on days 3-5 (FFM). The cycles were repeated every 21 days until progression, severe toxicity or patient refusal.. Of the 104 patients, 96 were evaluable for response and toxicity. The overall response rate was 43% (95% confidence interval 32.8-53.2%); 40 patients achieved stable disease (42%) and 15 progressed (15%). In a retrospectively defined subgroup of patients with clinical resistance to taxanes (12 patients) or anthracyclines (14 patients), the response rate was 42%. The median time to progression was 8 months (3-18 months), and the median overall survival was 10.5+ months (2-36 months). The most common treatment-related adverse events were stomatitis, neutropenia, nausea/vomiting and diarrhea. Stomatitis, neutropenia and thrombocytopenia were the only grade 4 treatment-related adverse events, and occurred in no more than 3% of patients.. The tested FFM regimen seems to offer a valid option for patients with metastatic breast cancer who have been pretreated with two or more chemotherapeutic lines or who have failed on regimens containing anthracyclines or taxanes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitomycin; Nausea; Neoplasm Metastasis; Neutropenia; Quality of Life; Stomatitis; Survival Rate; Treatment Outcome

We have investigated the efficacy, safety and quality of life profiles of three therapeutic combinations [irinotecan + leucovorin (LV)/5-fluorouracil (5-FU), oxaliplatin + LV/5-FU and irinotecan +oxaliplatin] in patients with metastatic colorectal cancer after failure of a 5-FU-based regimen, or whose disease had progressed within 6 months of the end of treatment.. One hundred and one patients were randomised to receive either: (i) irinotecan 180 mg/m(2) on day 1 followed by an LV 200 mg/m(2) infusion, before a 5-FU 400 mg/m(2) bolus followed by a 5-FU 600 mg/m(2) infusion (LV5FU2 regimen), on days 1 and 2 every 2 weeks; (ii) oxaliplatin 85 mg/m(2) on day 1 followed by the LV5FU2 regimen on days 1 and 2 every 2 weeks; or (iii) oxaliplatin 85 mg/m(2) followed by irinotecan 200 mg/m(2), both on day 1 every 3 weeks. The primary end point was overall response rate (ORR).. The intention-to-treat ORRs were 11.4% [95% confidence interval (CI) 3.2-26.7), 21.2% (95% CI 9.0-38.9) and 15.2% (95% CI 5.1-31.9), respectively, in the three arms. Tumour growth control was >or=60% for all three combinations and overall survivals were 12.2 months (95% CI 9.2-16.0), 11.5 months (95% CI 9.0-14.1) and 11.0 months (95% CI 8.1-12.2), respectively. All patients were evaluable for safety. Main grade 3-4 toxicity was neutropenia (33 to 39% of patients).. Thus, second-line treatment with irinotecan/LV5FU2, oxaliplatin/LV5FU2 or irinotecan/oxaliplatin, provides good tumour growth control and survival coupled with an acceptable safety profile.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Quality of Life; Survival; Treatment Outcome

Previous studies have shown that the taxane, docetaxel, is effective in treating gastric cancer. The aim of this study was to assess the efficacy and safety of docetaxel in combination with 5-fluorouracil (5-FU) and leucovorin (LV).. Thirty patients with histologically proven locally advanced and/or metastatic gastric cancer with WHO performance status 0-2 were enrolled and received either 75 or 100 mg/m(2) docetaxel as a 1-h intravenous infusion on day 1 every 28 days. All patients also received 5-FU (1800 mg/m(2)) plus LV (500 mg/m(2)), by continuous intravenous infusion over 24 h on days 1, 8, and 15 every 28 days. Chemotherapy was given for at least two cycles.. Of the 25 evaluable patients, 3 showed a complete response, 4 showed a partial response, and 11 patients had stable disease. The overall response rate was 28.0% (95% confidence interval [CI], 10.4, 45.6). The median time to progression was 5.9 months (95% CI, 5.4, 6.5), and the median overall survival was 7.7 months (95% CI, 7.2, 8.3) for the intent-to-treat population. The most frequent grade III and IV hematological toxicities were neutropenia and anemia. Febrile neutropenia was observed in 10% of patients and 2.4% of cycles. The prophylactic use of granulocyte colony-stimulating factor (G-CSF) in 3 patients reduced the incidence and severity of neutropenia. Other hematological toxicities were rare.. Docetaxel in combination with weekly 5-FU and LV is effective in treating patients with advanced/metastatic gastric cancer. This new docetaxel-containing combination shows promise as a third-generation treatment option for gastric cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Neoplasms; Disease Progression; Docetaxel; Female; Fluorouracil; Humans; Incidence; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Paclitaxel; Severity of Illness Index; Stomach Neoplasms; Survival Analysis; Taxoids; Time Factors; Treatment Outcome

Irinotecan (CPT-11) has been shown to prolong survival and improve quality of life in comparison to best supportive care in colorectal cancer patients with pretreatment of bolus 5-fluorouracil (5-FU). After first-line 24-h high-dose (HD) 5-FU/folinic acid (FA) an objective response rate of 11% with 3-weekly CPT-11 350 mg/m was reported. In the present study we investigated weekly CPT-11 in combination with 24-h HD-5-FU/FA as second-line treatment after prior exposure to 24-h HD-5-FU. Synergy between 5-FU and CPT-11 is the rationale to combine both substances for second-line therapy in order to overcome resistance to 5-FU. Thirty-five patients were recruited in a single institution to receive 6 x weekly CPT-11 80 mg/m(2), FA 200 mg/m(2) and 24-h HD-5-FU 2000 mg/m(2). Treatment was repeated on day 57.. M/F=20/15, median WHO performance status 1, range (0-2). Thirty-four patients were evaluable for response: partial response 17% and no change 40%. Median time to progression and overall survival were 3.3 and 8.4 months, respectively. All patients were evaluable for toxicity analysis (National Cancer Institute Common Toxicity Criteria grade 3): leukocytopenia 3%, diarrhea 12% and vomiting/nausea 6%. Of the assigned doses, a median 100% of 5-FU and 92% of CPT-11 were administered during the first cycle of chemotherapy. We conclude that weekly CPT-11 and HD-5-FU/FA is an active and safe combination chemotherapy resulting in response rates in the upper range of other CPT-11-based second-line regimen. The toxicity profile in our series compared to 3-weekly CPT-11 seems favorable.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Synergism; Female; Fluorouracil; Humans; Infusion Pumps, Implantable; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Treatment Failure

We investigated the activity of irinotecan given with a more convenient modified bimonthly de Gramont regimen of bolus and infusional 5-fluorouracil [IrMdG] in advanced or metastatic colorectal cancer in the first and second line setting. Irinotecan 180 mg m(-2) was infused over 90 min. L-folinic acid 175 mg or d,l folinic acid 350 mg was given over 2 h followed by a bolus of 5-fluorouracil (400 mg m(-2)) and a 46 h continuous infusion of 5-fluorouracil (2.4-2.8 g m(-2)). Forty-six previously untreated patients (Group A) and 36 who had received 5-fluorouracil for metastatic disease (Group B) were recruited. Seventy-eight patients were evaluable for response. A partial response was seen in 13 out of 43 (30% [95%CI 28.1-31.9%]) in Group A and 8/35 (23% [95% CI 17.9-28.1%]) in Group B. 40% (95%CI 38.1-41.9%) of Group A and 26% (95% CI 20.9-31.1%) of Group B patients achieved disease stabilisation. The median progression free survival from the start of this treatment was 7 months (95% CI 4.4-9.6 months) in Group A and 5 months (95% CI 2.8-7.2 months) in Group B. Median overall survival was 14 months (95% CI 9.0-18.9) in Group A and 11 months (95% CI 5.9-16.1) in Group B. Grade 3-4 toxicity in both treatment groups were similar; leucopenia 17% and diarrhoea 7-8%. Grade 3-4 mucositis was not seen and severe alopecia affected only three patients. IrMdG is an active and well-tolerated regimen for both the first and second line treatment of advanced colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Leukopenia; Male; Middle Aged; Mouth Mucosa; Neoplasm Metastasis; Stomatitis; Treatment Outcome

The purpose of this study was to evaluate the efficacy and tolerance of a combination of irinotecan, oxaliplatin, and 5-fluorouracil (5-FU)/leucovorin in advanced colorectal cancer (ACC). Twenty-six consecutive patients with ACC and an Eastern Cooperative Oncology Group performance status of 0-2 were treated with a combination of oxaliplatin (120 mg/m2 intravenously [i.v.] for 2 hours) on day 1, irinotecan (250 mg/m2 i.v. for 90 minutes) on day 1, and 5-FU (2600 mg/m2 plus leucovorin 500 mg/m2 i.v. in a 24-hour infusion) on day 1 and 15, every 4 weeks. Five of the patients (19.2%) had shown previous chemoresistance. One hundred sixty-two cycles were administered (median, 6; range, 3-13 cycles). All patients were evaluated for toxicity; 23 were evaluable for response. According to intention-to-treat, the overall response rate was 69.2% (18 patients; 95% CI: 48.2%-85.7%), including 3 complete remissions (11.5%). Four additional patients (15.3%) had stable disease, and only 1 (3.8%) progressed. Major toxicities were neutropenia and diarrhea. Grade 3 neutropenia occurred in 9 patients (34.6%), and grade 4 occurred in 1 patient (3.8%). Grade 3 diarrhea occurred in 8 patients (30.7%) and grade 4 in 1 patient (3.8%). Other toxicities were mild. After a median follow-up of 15.5 months, the median progression-free survival was 14 months. Seventeen patients (65.4%) are still alive, and the median overall survival has not been reached yet. This combination of irinotecan, oxaliplatin, and 5-FU/leucovorin is fairly well tolerated and shows promising activity in ACC. This treatment merits further comparison with other combination regimens.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Probability; Survival Analysis; Survival Rate; Treatment Outcome

Our study aims to further clarify the prognostic significance of p53 overexpression in stage IV colorectal cancer. Between January 1994 and June 1997, we recruited 144 patients with stage IV colorectal cancers for our study, based on appropriate eligibility criteria. The patients were nonrandomly allocated to 2 treatment groups of either with or without high-dose 5-fluorouracil plus leucovorin chemotherapy (HDFL: 5-Fu: 2,600 mg/m(2) leucovorin 300 mg/m maximum 500 mg). Each treatment group was further divided into 2 subgroups according to the status of p53 overexpression. Therefore, 4 subgroups were allocated in our study and were designated as p53 (overexpression) HDFL (+), n = 65; p53 (normal) HDFL (+), n = 37; p53 (overexpression) HDFL (-), n = 27; and p53 (normal) HDFL (-), n = 15, respectively. All patients were prospectively followed until April 2001. There was no significant difference of the background clinicopathologic data of these 4 allocated subgroups of patients (p > 0.05). Multivariate analysis of various clinicopathologic factors of the whole group of patients indicated that age > or = 60 years, poor differentiation, mucin production, CEA > 100 ng/ml, p53 overexpression and without chemotherapy were the significant independent poor prognostic factors (p < 0.05). Survival analyses indicated that the patients of subgroup p53 (normal) HDFL (+) survived significantly longer than those of subgroup p53 (overexpression) HDFL (+), with mean survival time (95% confidence interval [CI]) of 20.24 (16.24-24.25) and 13.29 (10.98-15.60) months, respectively (p = 0.0043, log-rank test). In contrast, in patients without chemotherapy, the prognosis was poor regardless of their p53 status, with mean survival time (95% CI) of 6.85 (5.47-8.23) and 5.87 (4.48-7.26) months in p53 (overexpression) HDFL (-) and p53 (normal) HDFL (-) subgroups of patients, respectively (p = 0.2820, log-rank test). Cancers of normal p53 expression responded significantly better to HDFL (p < 0.05), with mean response rate (95% CI) being 65.57% (52.18-82.96%) in subgroup p53 (normal) HDFL (+) as compared to 35.38% (23.52-47.24%) in subgroup p53 (overexpression) HDFL (+). The toxicity to HDFL was similarly minimal between p53-normal and p53-overexpression patients (p > 0.05). We thus concluded that the poorer prognosis of stage IV colorectal cancers with p53 overexpression was associated with their poorer chemosensitivity rather than the more biologic aggressiveness.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Biomarkers, Tumor; Carcinoembryonic Antigen; Cell Differentiation; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Genes, p53; Humans; Leucovorin; Life Tables; Mucins; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Staging; Palliative Care; Prognosis; Risk Factors; Survival Analysis; Thymidylate Synthase; Tumor Suppressor Protein p53

To define the cyclophosphamide (CTX) maximal tolerated dose when combined with fixed doses of gemcitabine, fluorouracil (5-FU) and folinic acid (leucovorin, LFA) in metastatic breast cancer patients pretreated with anthracyclines and taxanes.. Metastatic breast cancer patients aged < or = 75 years, with ECOG performance status 0-2, were eligible, provided that they had received previous anthracycline- and taxane-based chemotherapy for the advanced disease. Chemotherapy consisted of gemcitabine 1,000 mg/m(2), 5-FU 425 mg/m(2), LFA 100 mg/m(2) and escalating doses of CTX, starting from 500 mg/m(2), on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occurred in > 33% of patients of a given cohort. After the definition of DLT, a further escalation with the addition of granulocyte colony-stimulating factor (G-CSF; on days 3-5 and 10-12) was planned.. Since March 1999, 69 patients have entered this trial through seven different cohorts. The dose escalation was stopped at the CTX dose of 600 mg/m(2) since 3/6 patients showed DLT. A further dose escalation was attempted in the presence of G-CSF support. A CTX dose of 800 mg/m(2) proved to be safe and was chosen for the phase II. A total of 33 patients were treated at this dose level. The treatment was fairly well tolerated, grade 3-4 neutropenia and thrombocytopenia occurring in 38 and 16% of patients, respectively. No cases of sepsis or bleeding were registered. Four patients required a packed red blood cell transfusion. Severe nonhematologic toxicity was also uncommon, occurring in 10 patients. Three complete and 24 partial responses were recorded for an overall response rate of 38% (95% CI = 26-50). Two complete and 12 partial responses were recorded in the 33 patients treated in the phase II for an overall response rate (ORR) of 42% (95% CI = 25-61).. The gemcitabine-CTX-5-FU/LFA combination is a well-tolerated treatment for poor-prognosis breast cancer patients with previous exposure to anthracyclines and taxanes. With the addition of G-CSF, a cumulative CTX dose of 1,600 mg/m(2) can be safely delivered every 3 weeks. The evidence of an ORR approaching 40% is very promising and justifies further evaluations in this subset of patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Survival Rate; Taxoids

The combination of CPT-11 with 5-fluorouracil (5-FU) in advanced colorectal cancer (ACC) represents an attractive approach. A phase II study was conducted to assess the tolerance and efficacy of CPT-11 in combination with leucovorin-modulated bolus plus infusional 5-FU given according to the de Gramont regimen in chemonaive patients with ACC. Fifty-four patients with histologically confirmed ACC were enrolled. The patients' median age was 65 years; 30 (55.5%) patients were men; performance status (World Health Organization) was 0 in 27 (50%) patients, 1 in 22 (41%), and 2 in 5 (9%). Patients received leucovorin (200 mg/m2/d) as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at 400 mg/m2/d, and then as a 22-hour continuous infusion at 600 mg/m2/d, repeated on 2 consecutive days. CPT-11 (180 mg/m2; 30-minute intravenous infusion) was administered on day 1, simultaneously with leucovorin administration. This cycle was repeated every 2 weeks. Complete response was achieved in 4 patients (8%) and partial response in 19 (37%) (overall response rate: 45%; 95% CI: 24-50.5%). Stable disease was achieved in 16 (31%) patients and progressive disease in 13 (25%). The median duration of response and the median TTP were 5 and 8 months, respectively. After a median follow-up period of 11 months, 33 (61%) patients are still alive; the median overall survival has not yet been reached. Thrombocytopenia and anemia were very rare. Grade III/IV neutropenia developed in 19 patients (36%); febrile neutropenia developed in 4 patients, and 1 of them died of sepsis. Grade IV diarrhea was seen in 7 (13%) patients, and 4 of them required hospitalization. Grade III and IV mucositis was observed in two (4%) and one (2%) patients, respectively. Other toxicities were mild. The combination of CPT-11 and bolus plus infusional 5-FU is a relatively well-tolerated and effective first-line treatment in ACC. Final results from large phase III trials are awaited to clarify whether the CPT-11/5-FU combinations should be considered as "standard" first-line treatment in ACC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Remission Induction; Survival Analysis

Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs might act synergistically with mitomycin C, a randomized study using a 'pick the winner' design was undertaken to determine the effectiveness and tolerance of these two combination schedules in patients with fluoropyrimidine/leucovorin-pretreated advanced colorectal cancer.. Sixty-four patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin were enrolled onto this study. They were randomly assigned to treatment with irinotecan 120 mg/m2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 (arm A) or oxaliplatin 85 mg/M2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 (arm B). In both treatment arms, courses were repeated every 4 weeks.. The objective response rate in arm A is 7/33 (21.2%; 95% confidence interval, 9.0-38.9%) as compared to 5/31 in arm B (16.1%; 95% CI, 5.5-34.7%). Stable disease was noted in 48.5 vs. 45.2%, whereas the tumor progressed in 30.3 vs. 38.7%, respectively. Similar to the recorded response activities, the difference of the two combination regimens in terms of median time to progression (7.0 vs. 5.2 months) and overall survival (12.0 vs. 11.2 months) was only minor and clincally insignificant. The tolerance of treatment was acceptable in both arms, though severe adverse reactions requiring dose reductions (30 vs. 16%) and treatment delays (22 vs. 13% of courses) were more commonly noted with irinotecan/mitomycin C. The most common toxicities in arm A were neutropenia (85%; WHO grade 3/4 in 33%), thrombocytopenia (52%), diarrhea (45%), emesis (52%) and alopecia (92%). In arm B, common toxicities included neutropenia (68%; grade 3/4 in 13%), thrombocytopenia (81%), emesis (52%), and peripheral neutropathy (48%).. Both mitomycin C combination regimens seem to provide an acceptable therapeutic index in patients with fluoropyrimidine/leucovorin-pretreated metastatic colorectal cancer. In view of the increasing need for a broader chemotherapeutic armentarium for second-line therapy of this common malignant disease, both regimens may be worthwhile to undergo further clinical investigation.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Female; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Mitomycin; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Salvage Therapy; Treatment Outcome

To study tolerability and efficacy of an intensified chronomodulated schedule of fluorouracil (5-FU) and l-folinic acid (l-FA) as first-line treatment of metastatic colorectal cancer, 5-FU was given near individually determined dose-limiting toxicity in a multicenter phase II trial.. One hundred patients (68 men and 32 women, median age 62 years, World Health Organization performance status less-than-or-equal 2) with previously untreated and inoperable metastases received chronomodulated daily infusion of 5-FU/l-FA (from 10:00 PM to 10:00 AM with peak at 4:00 AM). 5-FU dose was escalated from 900 to 1,100 mg/m(2)/d with fixed dose of l-FA at 150 mg/m(2)/d for 4 days every 14 days.. 5-FU dose escalation was achieved in 66% of the patients. Grade 3 to 4 toxicities mainly consisted of nausea or vomiting (14% of patients and 1.5% of courses), hand-foot syndrome (38% of patients and 8% of courses), mucositis (26% of patients and 4% of courses), and diarrhea (21% of patients and 2.3% of courses). Objective response rate (ORR) was 41% (95% confidence interval, 31.5% to 50.5%). Twenty patients underwent metastases surgery; among these, 12 had a complete resection. Median progression-free survival was 7 months. Median survival was 17 months; 28% of the patients were alive at 2 years and 18.6% at 3 years.. The ORR achieved with intensified chronomodulated delivery of 5-FU/l-FA was nearly twice as high as that earlier obtained by our cooperative group using less intensive 5-FU/FA chronotherapy.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chronotherapy; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Rate

To compare the efficacy and tolerability of eniluracil (EU)/fluorouracil (5-FU) with that of 5-FU/leucovorin (LV) as first-line therapy for patients with metastatic/advanced colorectal cancer.. This multicenter, randomized, open-label, phase III study (FUMA3008) conducted in the United States and Canada compared the safety and efficacy of EU/5-FU (11.5 mg/m(2)/1.15 mg/m(2) twice daily for 28 days every 35 days) with that of intravenous 5-FU/LV (425 mg/m(2)/20 mg/m(2) once daily for 5 days every 28 days) in patients with previously untreated metastatic colorectal cancer. Overall survival (OS) was the primary end point.. A total of 981 patients were randomized and 964 patients received treatment (485 EU/5FU, 479 5FU/LV). Survival for EU/5-FU was not statistically equivalent (but not statistically inferior) to that for 5-FU/LV (hazard ratio, 0.880; 95% confidence interval [CI], 0.75 to 1.03). Median duration of survival was 13.3 months in the EU/5-FU group and 14.5 months in the 5-FU/LV group. Median duration of progression-free survival for EU/5-FU was statistically inferior to that of the control group (20.0 weeks [95% CI, 19.1 to 20.9 weeks] v 22.7 weeks [95% CI, 18.3 to 24.6 weeks]; P =.01). Both treatments were well tolerated. Diarrhea was the most common nonhematologic toxicity in both groups; treatment-related grade 3 or 4 diarrhea occurred in 19% of patients treated with EU/5-FU and 16% of patients receiving 5-FU/LV (P =.354). Grade 3 or 4 granulocytopenia occurred in 5% of EU/5-FU patients and 47% of 5-FU/LV patients.. Safety profiles of both treatments were acceptable. Although antitumor activity was observed, EU/5-FU did not meet the protocol-specified statistical criteria for equivalence to 5-FU/LV in terms of OS.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Survival Analysis; Treatment Outcome; Uracil

This phase II study was designed to evaluate the efficacy and toxicity of 3-h interval sequential methotrexate (MTX) and 5-fluorouracil (5-FU) with leucovorin (LV) rescue in the treatment of patients with metastatic colorectal cancer.. Forty-two patients with histologically confirmed metastatic colorectal cancer and at least one two-dimensionally measurable lesion, aged 30-74 years old, with performance status < or =2 and no or one prior chemotherapy were selected. Patients received sequential MTX 100 mg/m2 by bolus injection and 5-FU 600 mg/m2 at 3 h followed by LV rescue initiated after 24 h (15 mg per body every 6 h for six doses). The treatment was repeated every week or every 2 weeks until disease progression. All patients were treated as out-patients unless complications arose.. All 42 patients entered in this study were assessable both for response and toxicity. Fifteen patients achieved objective responses (one complete and 14 partial), for an overall response rate of 36% (95% CI: 11-51%). Response rates in pretreated patients and patients with naive chemotherapy were 27 and 42%, respectively. Sixteen patients had stable disease and 11 progressed with therapy. The median survival for all patients was 378 days. The hematological toxicity was mild with no grade 3/4 leukopenia. The major non-hematological toxicity was diarrhea (one grade 4, four grade 3).. This 3-h interval sequential MTX and 5-FU with LV rescue is an active regimen in patients with metastatic colorectal cancer. The treatment showed mild toxicity and was administered on an out-patient basis. The present findings suggest that this regimen warrants further investigation in patients with metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Survival Analysis; Treatment Outcome

This is a retrospective study of laryngeal preservation in endolaryngeal cancer with induction chemotherapy and radiotherapy for good responders. Between 1985 and 1995, 104 patients were treated in Institut Gustave Roussy (87 patients) and in Limoges (17 patients). The overall survival for the whole population was 76% and 69% at 3 and 5 years respectively, with a 36% rate of laryngeal preservation. In this retrospective series of patients, the single prognostic factor affecting survival was arytenoid mobility before treatment (66% and 55% at 3 years vs 85% and 82% at 5 years; p<0.004). Loco-regional failures were higher (33% vs 15%, p<0.03), and laryngeal preservation was lower (18% vs 51%) among patients with a fixed arytenoid (49 pts), compared with patients with a non fixed arytenoid (55 pts) ). The percentages of patients with a fixed arytenoid could explain the conflicting results of the two randomized studies of laryngeal preservation in laryngeal cancer.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arytenoid Cartilage; Bleomycin; Cisplatin; Combined Modality Therapy; Data Interpretation, Statistical; Fluorouracil; Humans; Laryngeal Neoplasms; Laryngectomy; Leucovorin; Lymphatic Metastasis; Neoplasm Metastasis; Prognosis; Radiotherapy Dosage; Retrospective Studies; Survival Analysis; Time Factors

To evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with oxaliplatin (L-OHP) plus fluorouracil (5-FU)/leucovorin (LV) (de Gramont regimen) as first-line treatment of metastatic colorectal cancer (MCC).. Thirty-one patients with MCC who had not received prior therapy for metastatic disease were enrolled. Their median age was 60 years; performance status (World Health Organization) was 0 in 12, 1 in 14, and 2 in five patients; 19 patients (61%) had prior surgery, and 14 (45%) had adjuvant chemotherapy. CPT-11 was administered on day 1 at 150 mg/m(2) as a 90-minute intravenous (IV) infusion; L-OHP was administered on day 2 at 65 mg/m(2) as a 2-hour IV infusion; and on days 2 and 3, LV 200 mg/m(2) preceded 5-FU administration of 400 mg/m(2)/d initial IV bolus dose followed by 600 mg/m(2)/d 22-hour IV continuous infusion. The regimen was repeated every 2 weeks.. All patients were assessable for toxicity and 30 for response to treatment. Complete response was achieved in two patients (6.5%) and partial response in 16 (51.6%) (overall response rate, 58.1%; 95% confidence interval, 40.7% to 75.4%); eight patients (25.8%) had stable disease, and five (16.1%) had disease progression. The median duration of response was 9 months, and the median time to disease progression was 13 months. Neutropenia grade 3 to 4 occurred in 14 patients (45%) and febrile neutropenia in two (6%). Diarrhea grade 3 to 4 was observed in 10 patients (32%), neurotoxicity grade 3 to 4 in three (9%), and asthenia grade 3 in two (10%). No treatment-related death has occurred.. The triplet combination of 5-FU/LV + CPT-11 + L-OHP is a highly active regimen with manageable toxicity as front-line treatment in MCC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Patient Compliance; Quality of Life; Survival Analysis

The clinical value and costs of different diagnostic tools used to identify potentially curable recurrent disease in patients treated adjuvantly for curatively resected Dukes' C colonic cancer were examined.. The study group comprised 496 patients treated with chemotherapy over a 1-year interval. Follow-up consisted of interim history, physical examination, liver ultrasonography or computed tomography (CT), measurement of carcinoembryonic antigen (CEA) levels, chest radiography and colonoscopy.. Two hundred and thirteen patients had recurrent disease (median follow-up 43 months). Forty-two patients with recurrence (20 per cent) were treated with curative intent (median survival 38 months; 5-year survival rate 40 per cent). Recurrence was identified by liver ultrasonography or CT (n = 14), evaluation of symptoms (n = 12), colonoscopy (n = 8), CEA measurement (n = 3), chest radiography (n = 2), physical examination (n = 1) and other modalities in two patients. The mean cost of diagnostic procedures per curative resected recurrence for patients amenable to salvage surgery was US$9011. Of all treatable recurrences, 12 of 42 were identified by evaluation of symptoms only. Ultrasonography and colonoscopy identified 22 recurrences at a cost of US$11 790 per patient, while routine follow-up by CEA measurement, chest radiography and physical examination identified a further six at a cost of US$19 850 per patient.. Potentially curable recurrences were detected primarily by liver imaging and colonoscopy. The yield of CEA measurement, chest radiography and physical examination was relatively low; such methods were expensive and should not be recommended in the routine follow-up of these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Colonic Neoplasms; Costs and Cost Analysis; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Levamisole; Liver Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Physical Examination; Survival Analysis; Tomography, X-Ray Computed; Ultrasonography

Irinotecan is a topoisomerase I inhibitor that prolongs survival in patients with colorectal cancer refractory to fluorouracil (5-FU) and leucovorin (LV). This demonstrated activity of irinotecan as effective second-line therapy for colorectal cancer led to evaluation of combination irinotecan/5-FU/LV as first-line therapy for patients with metastatic disease. The results of two prospective phase III randomized, controlled, multicenter, multinational clinical trials in patients with previously untreated metastatic colorectal cancer served as the basis for U.S. and European approval of irinotecan/5-FU/LV for this indication. An overview of the findings of these two pivotal studies provides insights regarding the application of this new combination in clinical practice.. Patients were randomly assigned to receive 5-FU/LV, either alone, or with concurrent irinotecan. The study conducted primarily in North America (study 1), employed bolus 5-FU/LV schedules, while the study performed primarily in Europe (study 2), employed infusional 5-FU/LV regimens. Major endpoints included tumor response rate, time to tumor progression (TTP), overall survival, quality of life, and safety.. In study 1, the respective confirmed response rates for irinotecan/5-FU/LV versus 5-FU/LV were 39% and 21% (p <.001); median TTPs were 7.0 months and 4.3 months, respectively (p =.004). In study 2, response rates for irinotecan/5-FU/LV versus 5-FU/LV alone were 35% and 22% (p =.005); median TTPs were 6.7 months and 4.4 months, respectively (p <.001). Survival time increased significantly with irinotecan/5-FU/LV versus 5-FU/LV alone in both studies (study 1: median 14.8 months versus 12.6 months, p =.042; study 2: median 17.4 months versus 14.1 months, p =.032). The combined analysis of the data from the two studies showed median survivals of 15.9 months versus 13.3 months, favoring the irinotecan-containing combinations (stratified-by-study p =.003). Patients in study 1 had a 36% lower risk of tumor progression and a 20% lower risk of death with the irinotecan combination than with 5-FU/LV alone; comparable risk reduction values in study 2 were 42% and 23%. While grade 3 diarrhea and vomiting were more common with irinotecan/5-FU/LV, grade 4 neutropenia, neutropenic fever, and mucositis were less common with irinotecan/5-FU/LV than with the Mayo Clinic 5-FU/LV regimen.. The combination of irinotecan/5-FU/LV is superior to 5-FU/LV alone as first-line therapy for patients with metastatic colorectal cancer, offering consistently improved tumor control and prolonged survival. Irinotecan-based combination therapy sets a new survival standard for the treatment of this life-threatening disease.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Treatment Outcome

Unresectable colorectal liver metastases are a significant clinical problem. Isolated hepatic perfusion (IHP) is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating liver tumors. This study presents our results of IHP with tumor necrosis factor (TNF) plus melphalan or IHP with melphalan alone followed by infusional floxuridine (FUDR) and leucovorin in patients with advanced or refractory unresectable hepatic colorectal metastases.. Fifty-one patients with unresectable colorectal hepatic metastases underwent a 60-minute IHP with 1.5 mg/kg melphalan and hyperthermia (39 degrees C to 40 degrees C). Thirty-two patients received IHP with 1 mg TNF with melphalan and 19 patients had IHP with melphalan alone followed by monthly hepatic intra-arterial infusional (HAI) FUDR (0.2 mg/kg/day) and leucovorin (15 mg/M(2)/day) for 14 days monthly for up to 12 months. Twenty-six patients failed 1 or more previous treatment regimens for established hepatic metastases and 27 had greater than 25% hepatic replacement (PHR) by tumor. Patients were monitored for response, toxicity, and survival.. There was 1 perioperative death (2%), and only 2 patients (4%) had measurable perfusate leak during IHP (both less than 4%). In the 32 patients treated with IHP alone there were no detectable systemic TNF or melphalan levels during perfusion. The overall objective radiographic response rate (all partial [PR]) was 76% (38 of 50 assessable patients) with a median duration of 10.5 months (range, 2 to 21 months). Twenty-four of 31 patients (77%) had a PR after IHP alone and 14 of 19 (74%) after IHP with postperfusion HAI. Median duration of response was 8.5 months after IHP alone and 14.5 months after IHP and HAI; median survival was 16 and 27 months, respectively. There were 18 PRs in 26 patients (69%) whose prior therapy had failed and 18 PRs in 27 patients (67%) with PHR of 25 or greater.. IHP can be performed with acceptably low morbidity and has significant antitumor activity in patients with unresectable hepatic metastases from colorectal cancer including those with refractory disease or PHR of 25 or greater. HAI appears to prolong the duration of response after IHP, and this combined treatment strategy deserves additional clinical evaluation as a therapeutic modality in this setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Floxuridine; Humans; Hyperthermia, Induced; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Radiography; Survival Analysis; Tumor Necrosis Factor-alpha

Irinotecan (CPT-11) is an active drug in the treatment of patients with advanced colorectal carcinoma. The infusion of 5-fluorouracil (5-FU) according to circadian rhythms was used previously to decrease toxicity and to increase its therapeutic efficacy. The objective of this study was to establish the maximum tolerated dose (MTD) of CPT-11 together with a chronomodulated infusion of 5-FU and the l-form of folinic acid (FA). Secondary end points were the assessment of activity and quality of life (QoL).. Twenty-six patients with advanced colorectal carcinoma who had received previous treatment with 5-FU were entered on this Phase I study. At least three patients were recruited at each dose level. The CPT-11 starting dose was 175 mg/m(2) on Day 1 with an increase of 50 mg/m2 per dose level. A daily administration of chronomodulated 5-FU (900 mg/m2; peak delivery rate at 04:00) and FA (175 mg/m2; peak delivery rate at 04:00) for 5 days every 3 weeks was given with CPT-11. After the first three patients, the 5-FU dose was reduced to 700 mg/m2 per day due to toxicity. No intrapatient dose escalation was allowed.. One hundred sixty-one courses were delivered. Dose-limiting toxicity was observed during the first course in seven patients (27%). Four patients developed neutropenia, with one patient reporting febrile neutropenia, two patients reporting severe stomatitis, and six patients reporting severe diarrhea. CPT-11 MTD was reached at 350 mg/m2 when a toxic death was observed with a recommended dose of 325 mg/m2. Six partial responses were observed (23%). The median duration of response and the progression free and overall survival rates were 199 days, 175 days, and 359 days, respectively. QoL was not affected by the treatment.. The recommended dose for Phase II trials is 325 mg/m2 CPT-11 on Day 1, which is similar to the dose given as a single agent, together with a 5-day chronomodulated infusion of 700 mg/m2 5-FU and 175 mg/m2 FA. Intensification of this schedule every 2 weeks should be achievable.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chronotherapy; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Quality of Life

The aim of the study was to investigate the possibility of dual modulation of UFT with leucovorin and hydroxyurea in a phase II trial of metastatic colorectal cancer. A total of 77 patients with measurable disease were included. UFT (300 mg/m2) was given with a fixed dose of 1-leucovorin (22.5 mg daily) and hydroxyurea (0.5 g daily) for 28 days followed by a 7 days' rest period. Treatment continued until progression or unacceptable toxicity. Sixty-three patients were evaluable for response. One patient (1.6%) had a complete remission and 13 (20.6%) a partial response for an overall response rate of 22.2%. The treatment was well tolerated. No significant bone marrow depression occurred. Grade 2 gastrointestinal toxicity was recorded in 28.5% of the patients, and grade 3 in 12.9%. The median time to progression was 6.8 months and the median crude survival was 11 months. In conclusion, hydroxyurea did not appear to increase either the response rate or the toxicity. Phase III trials along the same line cannot be recommended.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Interactions; Female; Humans; Hydroxyurea; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Tegafur; Uracil

The aim of this study was to examine the efficacy and safety of both oxaliplatin as a single agent and oxaliplatin in combination with dailyx5 bolus 5-fluorouracil and folinic acid (5-FU/FA, Mayo clinic regimen) in the first-line treatment of metastatic colorectal cancer (CRC) patients. 73 advanced CRC patients were randomised to receive either oxaliplatin 85 mg/m(2) every 2 weeks (35 patients), or the same treatment combined with 5-FU 425 mg/m(2)/day and FA 20 mg/m(2)/dayx5 days every 4 weeks (38 patients). Treatment was continued until disease progression or unacceptable toxicity. All patients had documented inoperable disease and no previous chemotherapy for advanced disease. Based on the investigators' assessment of best response, objective response rate was 9% (95% confidence interval (CI) 2-24%) in the oxaliplatin arm, and 45% (95% CI 27-64%) in the oxaliplatin+5-FU/FA arm. Median progression-free survival (PFS) was 2 months (95% CI 1.7-2.4 months) in the oxaliplatin arm and 3.9 months (95% CI 2.9-5 months) in the oxaliplatin+5-FU/FA arm. Severe neutropenia was seen in 23% of patients in the oxaliplatin+5-FU/FA arm, and none in the oxaliplatin arm. There were two treatment-related deaths, both in the oxaliplatin+5-FU/FA arm. In the oxaliplatin+5-FU/FA arm, severe diarrhoea, vomiting and stomatitis were seen in 34, 14 and 14% of the patients, respectively. In conclusion, oxaliplatin at a dose of 85 mg/m(2) given every 2 weeks was well tolerated and has limited activity in metastatic CRC, while the combination of this treatment with the full-dose Mayo clinic regimen (5-FU bolus 425 mg/m(2)/day+FA 20 mg/m(2)/dayx5 days every 4 weeks), although active, was unfeasible due to a high level of myelosuppression and gastrointestinal toxicity. Alternative lower dosing or other regimens are to be explored to ascertain the value of bolus 5-FU/FA combined with oxaliplatin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Treatment Outcome

Both OHP and 5-FU are clinically active as single agents in the treatment of metastatic colorectal cancer (MCRC). Clinical and laboratory studies suggest a synergistic interaction between these agents. This phase II study was performed to evaluate the activity of a schedule including OHP and protracted 5-FU infusion in 5-FU-resistant MCRC.. From October 1997 to January 2000, 50 patients with measurable progressive MCRC after one or more 5-FU-based regimens were treated. OHP (2-3-hour i.v. infusion) on day 1 and 5-FU (protracted i.v. infusion using elastomeric/electronic pump through a central venous catheter) on days 1-21 were administered every 3 weeks, at the following 4 dose levels: 1) OHP 100 mg/m2 + 5-FU 200 mg/m2 (21 patients); 2) OHP 100 mg/m2 + 5-FU 250 mg/m2 (3 patients); 3) OHP 130 mg/m2 + 5-FU 200 mg/m2 (10 patients); 4) OHP 130 mg/m2 + 5-FU 250 mg/m2 (6 patients).. Objective responses were 1 (2%) CR; 10 (20%) PR, for a median duration of 8 months; 23 (46%) stable diseases, for a median duration of 6 months: 16 (32%) progressions. CR + PR was higher in patients who had previously received no more than one line of chemotherapy for metastatic disease as compared with patients who had received two or more lines of therapy (33% vs. 5%, P < 0.01). The median time to progression was four months (one to nine). All dose levels (313 cycles) were well tolerated with mild toxicity. Major toxicity (grade 3 WHO) included: anaemia in 1 patient (2%), nausea and vomiting in 1 patient (2%), diarrhoea in 4 patients (8%) and stomatitis in 1 patient (2%); grade I and 2 peripheral neuropathy were encountered, respectively, in 30 (60%) and 8 (16%) patients. The median survival was 13 months (9-17), with 32 patients still alive after a median follow-up of 8 months.. This study suggests that 1) OHP plus protracted 5-FU infusion is an active combination in MCRC patients resistant to pre-treatment bolus 5-FU; 2) it has a good tolerability profile and 3) the optimum dose level is OHP 130 mg/m2 and 5-FU 250 mg/m2.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Survival Rate

To identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oxaliplatin (L-OHP) given on a weekly schedule including fixed doses of leucovorin (LV) and infusional 5-fluorouracil (5-FU), to define the toxicity profile of this regimen and to find preliminary evidence of its activity in pretreated patients with metastatic colorectal cancer (MCRC).. Twenty-one patients with progressive disease, treated with fluoropyrimidines and with histologically measurable MCRC entered into this phase I study. Fixed doses of LV (500 mg/m2) followed by a 48-hour 5-FU 2600 mg/m2 infusion (5-FU48h) were administered with escalating doses of L-OHP, starting from 60 mg/m2 and with stepwise increments of 5 mg/m2. No intra-patient dose escalation was allowed. Treatment was given once a week for four consecutive weeks, followed by a one-week rest period.. Three dose levels were tested. The MTD was L-OHP 70 mg/m2 since two of the three patients showed dose-limiting diarrhea and the third developed neutropenia during the first cycle of chemotherapy. Most patients complained of mild peripheral sensitive neurotoxicity, which was related to the cumulative dose of L-OHP. Treatment delays were necessary for a total of 42 cases, but only in II of 42 after the pre-arranged 10% dose reduction of 5-FU (2300 mg/m2). Sixteen patients were evaluable for response: seven (33%; 95% confidence interval (CI): 14.6%-57.0%) were considered to show a major response (one complete), six showed a stable disease, and in addition progressive disease was observed in three patients.. Our results show that L-OHP, LV and 5-FU can be administered safely and repetitively using a weekly schedule. Diarrhea and neutropenia are the DLT of this regimen. Its activity and its manageable toxicity profile deserve further evaluation in chemotherapy-naïve MCRC patients. The doses recommended for phase II trials are: L-OHP 65 mg/m2, LV 500 mg/m2 and 5-FU48h 2300 mg/m2 infusion given on a weekly-times-four schedule followed by a one-week rest period.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases

To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan's maximum-tolerated dose (MTD).. Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle.. Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P <.05) when irinotecan preceded 5-FU.. The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Enzyme Inhibitors; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

We sought to define the recommended dose of cyclophosphamide (CTX) for subsequent phase II assessment when combined with fixed doses of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and 5-fluorouracil/folinic acid in metastatic breast cancer patients previously treated with anthracyclines and taxanes. Patients age 70 or less, with an Eastern Cooperative Oncology Group performance status 0 to 2, were enrolled. Patients received gemcitabine 1,000 mg/m(2), 5-fluorouracil 425 mg/m(2), folinic acid 100 mg/m(2), and escalating doses of CTX (in 100-mg/m(2) increments), starting at 500 mg/m(2), on days 1 and 8 every 3 weeks. Since March 1999, 46 patients, with a median age of 51 years (range, 38 to 74 years), entered the trial in seven cohorts. Cyclophosphamide dose escalation was stopped at 600 mg/m(2) when three of six patients experienced dose-limiting toxicity (one each with grade 3 thrombocytopenia, grade 3 neutropenia, and persistent grade 2 neutropenia), and then continued with granulocyte colony-stimulating factor support. The CTX dose of 800 mg/m(2) was proven safe and was chosen for phase II study. Two complete and 15 partial responses provided an overall response rate of 37% (95% confidence interval, 23% to 51%). Gemcitabine/CTX/5-fluorouracil/folinic acid is well tolerated by metastatic breast cancer patients pretreated with anthracyclines/taxanes, up to a CTX dose of 800 mg/m(2). The phase II study is ongoing. Semin Oncol 28 (suppl 10):50-56.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel

A phase II study was performed to evaluate 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil (UFT) and leucovorin as first-line chemotherapy in European patients with advanced gastric cancer. From 38 patients, 25 were evaluable for response and 36 for toxicity. Patients received UFT at 300 mg/m(2)/day for 28 days, every 35 days and leucovorin at 90 mg/day on an identical schedule. Overall response rate was 10.5% (95% confidence interval (CI): 3.7-22.5%) in intent-to-treat analysis and 16% (95% CI: 5.7-33%) in evaluable patients. Grade 3-4 common toxicity criteria (CTC) toxicities were diarrhoea (28%; 10/36), nausea (11%; 4/36), vomiting (8%; 3/36) and asthenia (11%; 4/36). 23 patients in 44% (42/96) of the courses had to skip days of treatment due to toxicity or to non-compliance. In conclusion, UFT+leucovorin has a definitive, but low, efficacy in advanced gastric cancer patients. Toxicities were mainly gastrointestinal and treatment needs to be withheld if grade 2 diarrhoea occurs.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Stomach Neoplasms; Survival Analysis; Tegafur; Treatment Outcome; Uracil

The purpose of this study was to evaluate the activity and tolerance of high-dose leucovorin (LV) and infusional 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) as salvage chemotherapy in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. 41 patients (median age 59 years) with MBC refractory or resistant to anthracyclines and taxanes were enrolled. The patients' performance status (WHO) was 0 in 10 patients (24%), 1 in 22 (54%), and 2 in 9 (22%). 30 (73%) patients had received 2 or more prior chemotherapy regimens. Cyclophosphamide (600 mg m(-2)) was given i.v. bolus on day 1 and LV (500 mg m(-2) d(-1)) as a 2-h infusion followed by 5-FU (1.5 g m(-2) d(-1)) over a 22 h c.i. for 2 consecutive days. Cyclophosphamide was administered every 28 days while 5-FU/LV every 14 days. In an intention-to-treat analysis, complete response (CR) was achieved in 2 (4.9%) patients and partial response (PR) in 9 (22%) (overall response rate 26.9%; 95% CI: 13.27-40.39%). Stable disease (SD) and progressive disease (PD) were observed in 9 (22%) and 21 (51%) patients, respectively. The overall response rate was 6% and 40% in patients with primary and secondary resistance to anthracyclines/taxanes, respectively (P = 0.047). The median duration of response and the median time to disease progression was 8 and 9.5 months, respectively. The median overall survival was 13 months and the probability for 1-year survival 51%. Grade 3/4 neutropenia occurred in 9 (22%) patients and 4 (9%) patients developed grade 3/4 thrombocytopenia. Non-haematological toxicity was mild. There were no cases of febrile neutropenia, toxic deaths or treatment-related hospital admissions due to toxicity. The combination of high-dose 5-FU/LV with conventional doses of cyclophosphamide is a well tolerated and effective salvage regimen in patients with MBC heavily pretreated with both anthracyclines and taxanes.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Survival Rate; Taxoids; Treatment Outcome

A phase II study was performed to evaluate the activity and toxicity of 5-fluorouracil (5-FU), leucovorin, and inteferon alpha-2a in metastatic pancreatic carcinoma. Twenty-three patients were entered in this study. Four patients withdrew before receiving treatment and one patient was nonevaluable for response because of treatment-related toxicity. The most common significant toxicity was nausea and vomiting. Treatment-related hospitalization was significant. Of 18 evaluable patients, 4 maintained stable disease and 14 had disease progression. None had an objective clinical response. We conclude that this biochemically modulated 5-FU regimen is ineffective treatment for advanced pancreatic carcinoma, with significant toxicity even in highly selected patients with an ambulatory performance status.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Recombinant Proteins

Twelve women with metastatic breast cancer were treated with continuous infusion high dose leucovorin, 5-fluorouracil and cisplatin. Toxicity was severe although the dose was lower than previously described for the treatment of other cancers, and there was little anti-tumor activity. Many other regimens are more effective and less toxic.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis

The aim of this study was to evaluate the efficacy and toxicity of ifosfamide, 5-fluorouracil (5-FU) and leucovorin (IFL) as a second-line chemotherapy regimen in patients with recurrent undifferentiated nasopharyngeal carcinoma (NPC) previously treated with platinum/5-FU. Between June 1997 and February 1999, 18 patients were entered into the study. 3 patients had loco-regional recurrence, 12 had distant metastases and 3 had both loco-regional recurrence and distant metastases. All patients had previously received platinum/5-FU as adjuvant or palliative treatments. The IFL regimen consisting of ifosfamide 1.2 g/m(2) (with mesna), 5-FU 375 mg/m(2) and leucovorin 20 mg/m(2) for 5 days and was repeated every 21 days. The dose of ifosfamide was escalated to 1.4 and 1.6 g/m(2) in subsequent cycles according to the bone marrow toxicity, and the dose of 5-FU to 450 and 525 mg/m(2) according to the severity of mucositis. Patients received a median of 3 cycles of IFL (range: 2-6), with a median total ifosfamide dose of 21 g/m(2) (range: 13-46) and a median total 5-FU dose of 6.75 g/m(2) (range: 4.1-14.7). The median follow-up was 10 months (range: 4-25). 9 patients (50%) achieved a partial response and 1 patient (6%) achieved a complete response, with an overall response rate of 56% (95% confidence interval (CI): 32-80%). For those patients who responded to IFL, 8 had subsequent disease progression on follow-up, with a median response duration of 7.1 months (95% CI: 5.3-8.9). The median time to progression for all patients was 6.5 months (95% CI: 4.2-8.7). 12 patients are still alive with an estimated 1-year survival probability rate of 51%. Treatments were well tolerated, only 1 patient had grade 3 emesis. None of the patients had grade 3/4 anaemia, leucopenia or thrombocytopenia, although IFL was discontinued in 1 patient because of persisting thrombocytopenia. IFL is an effective second-line regimen in patients with recurrent NPC and is well tolerated with mild toxicity. Combining platinum and IFL in chemonaïve patients may further improve the overall response rate and duration and is worth investigating in future trials.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Follow-Up Studies; Humans; Ifosfamide; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Platinum Compounds; Tomography, X-Ray Computed

This study was performed to investigate the activity and safety of high dose 5-fluorouracil (5-FU) given as a weekly 24-hour infusion in combination with folinic acid plus mitomycin C in patients with advanced gastric cancer.. Chemonaive patients with locally advanced inoperable, recurrent or metastatic gastric cancer were treated with 15 mg/m(2) i.v. mitomycin C as bolus on day 1 of a 7-week cycle followed by a 2-hour infusion of folinic acid (500 mg/m(2)) and a 24-hour infusion of 5-FU (2,600 mg/m(2)) given on days 1, 8, 15, 22, 29, and 36 as outpatient treatment.. Thirty evaluable patients (median age 58 years and median ECOG performance status 1) received 1-4 cycles (median 3). 53% of the patients had liver metastases. Treatment-related toxicity was low with 10% of patients experiencing diarrhea >/=grade 3, 3% mucositis grade 3 and 3% nausea grade 3 (CTC). Hematological toxicity was mild with 13% thrombopenia grade 3 and no leukopenia grade 4. Eleven patients achieved a partial remission (major response rate 37%; 95% confidence interval 22-53%). Median time to progression was 5 months and median overall survival time was 7 months.. This regimen is a well-tolerated outpatient treatment for patients with advanced gastric cancer with efficacy being comparable to other chemotherapy protocols.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Neoplasm Metastasis; Stomach Neoplasms

To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis.. Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200-1500 mg/m2, followed by a 23-h infusion of 800-6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease.. Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 microM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 +/- 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 +/- 41 ml/min per m2) versus without CNS disease (59 +/- 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF.. This trial demonstrates that potentially cytotoxic CSF MTX concentrations (> 1 microM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.

Topics: Adult; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Leucovorin; Lung Neoplasms; Male; Meningeal Neoplasms; Methotrexate; Neoplasm Metastasis; Osteosarcoma

The rest/activity circadian cycle has been used as a reference for chemotherapy administration at specific times to improve tolerability and efficacy. Because cancer processes may be associated with alterations of circadian rhythms, the rest/activity cycle was monitored noninvasively to assess its relationship with tumor response, survival, and quality of life in 200 patients with metastatic colorectal cancer. Patients wore an actigraph, a wristwatch that records the number of accelerations per minute, for 3 days before receiving chronomodulated chemotherapy. The circadian rhythms in activity were estimated by two robust parameters: the autocorrelation coefficient at 24 h (r24), and the dichotomy index (I

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Circadian Rhythm; Colorectal Neoplasms; Drug Administration Schedule; Fatigue; Female; Fluorouracil; Humans; Hydrocortisone; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Quality of Life; Severity of Illness Index; Sleep Wake Disorders; Survival Analysis; Treatment Outcome

The combination of fluorouracil and leucovorin has until recently been standard therapy for metastatic colorectal cancer. Irinotecan prolongs survival in patients with colorectal cancer that is refractory to treatment with fluorouracil and leucovorin. In a multicenter trial, we compared a combination of irinotecan, fluorouracil and leucovorin with bolus doses of fluorouracil and leucovorin as first-line therapy for metastatic colorectal cancer. A third group of patients received irinotecan alone.. Patients were randomly assigned to receive irinotecan (125 mg per square meter of body-surface area intravenously), fluorouracil (500 mg per square meter as an intravenous bolus), and leucovorin (20 mg per square meter as an intravenous bolus) weekly for four weeks every six weeks; fluorouracil (425 mg per square meter as an intravenous bolus) and leucovorin (20 mg per square meter as an intravenous bolus) daily for five consecutive days every four weeks; or irinotecan alone (125 mg per square meter intravenously) weekly for four weeks every six weeks. End points included progression-free survival and overall survival.. Of 683 patients, 231 were assigned to receive irinotecan, fluorouracil, and leucovorin; 226 to receive fluorouracil and leucovorin; and 226 to receive irinotecan alone. In an intention-to-treat analysis, as compared with treatment with fluorouracil and leucovorin, treatment with irinotecan, fluorouracil, and leucovorin resulted in significantly longer progression-free survival (median, 7.0 vs. 4.3 months; P=0.004), a higher rate of confirmed response (39 percent vs. 21 percent, P<0.001), and longer overall survival (median, 14.8 vs. 12.6 months; P=0.04). Results for irinotecan alone were similar to those for fluorouracil and leucovorin. Grade 3 (severe) diarrhea was more common during treatment with irinotecan, fluorouracil, and leucovorin than during treatment with fluorouracil and leucovorin, but the incidence of grade 4 (life-threatening) diarrhea was similar in the two groups (<8 percent). Grade 3 or 4 mucositis, grade 4 neutropenia, and neutropenic fever were less frequent during treatment with irinotecan, fluorouracil, and leucovorin. Adding irinotecan to the regimen of fluorouracil and leucovorin did not compromise the quality of life.. Weekly treatment with irinotecan plus fluorouracil and leucovorin is superior to a widely used regimen of fluorouracil and leucovorin for metastatic colorectal cancer in terms of progression-free survival and overall survival.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Mouth Mucosa; Neoplasm Metastasis; Neutropenia; Proportional Hazards Models; Quality of Life; Stomatitis; Survival Analysis

A phase II study was carried out to evaluate the efficacy and toxicity of a double biochemical modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and leucovorin (LV) in patients with advanced unresectable colorectal cancer. Forty-two patients with measurable metastases of colorectal cancer were treated with 5-FU in daily doses of 600 mg/m2 given in a 6-hour intravenous (i.v.) infusion on days 1-5, LV 50 mg/m2 i.v. on days 2,3 and 5, and MTX 40 mg/m2 i.v. on days 1 and 4, every 4 weeks. Twenty-eight patients had a single metastatic site, eleven double, whereas three had more than two metastatic sites. Objective response (one complete response) was observed in 12 of 40 patients (30%) (95% confidence interval 16-48), stable disease in 19 patients (47%) and progression in 9 patients (23%). Overall median survival was 12 months. Median time to progression was 6 months. Treatment was generally well tolerated. The most frequent adverse reactions were stomatitis (38%), nausea and vomiting (35%), diarrhea (31%), leukopenia (18%), and plantar-palmar erythroderma (15%). The combination of 5-FU, LV and MTX seems to be an active regimen in advanced colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Survival Analysis

Studies of bimonthly 48-hour regimens of high-dose leucovorin (LV) (FOLinic acid), 5-fluorouracil (5-FU) by continuous infusion combined with OXaliplatin (FOLFOX) in pretreated patients with metastatic colorectal cancer suggest that oxaliplatin dose intensity is an important prognostic factor for response rate and progression-free survival (PFS). To help define the optimal dose schedule for oxaliplatin in pretreated metastatic colorectal cancer, we retrospectively analyzed data from three phase II studies using different FOLFOX regimens (FOLFOX2, 3 and 6).. Data on 126/161 patients were analyzed. FOLFOX2 included oxaliplatin 100 mg/m2; FOLFOX3, 85 mg/m2; and FOLFOX6, 100 mg/m2 (added to a simplified LV-5-FU regimen), all as two-hour infusions. A total of 47 patients received low dose intensity oxaliplatin (LDI: < or = 85 mg/m2/2 weeks) and 79 patients high dose intensity oxaliplatin (HDI: > 85 mg/m2/2 weeks).. Objective responses occurred in 31 (39%) HDI patients and 9 (19%) LDI patients (P = 0.03). Median PFS was 28 weeks, with 52% of HDI patients progression free at 6 months, and 26 weeks with 36% of LDI patients progression free at six months (P = 0.02). Increased oxaliplatin dose intensity was not associated with increased neurotoxicity or other toxicities. FOLFOX are among the most effective regimens for treating LV-5-FU-resistant metastatic colorectal cancer.. This study shows that oxaliplatin dose intensification significantly improves response rate and PFS in pretreated metastatic disease without increasing severe toxicity.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Gastrointestinal Diseases; Humans; Infusions, Intravenous; Leucovorin; Life Tables; Male; Middle Aged; Neoplasm Metastasis; Nervous System Diseases; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Prognosis; Remission Induction; Retrospective Studies; Salvage Therapy; Treatment Outcome

Leucovorin modulates the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. 24-hour infusion of 5-FU has been shown to enhance antitumor activity in colorectal cancer compared to bolus infusion. According to experimental data cyclophosphamide and tamoxifen may enhance the effectiveness of leucovorin and 5-FU. A phase II trial was initiated to evaluate the effect of a combination of low-dose cyclophosphamide (C), leucovorin (L), 5-FU (F) and tamoxifen (T) (CLFT) in advanced pancreatic cancer. Fifty patients were treated monthly with 300 mg/m2 cyclophosphamide and weekly with 500 mg/m2 leucovorin followed by a 24-hour infusion of 2000 mg/m2 5-FU and tamoxifen 20 mg bid. Three patients had a partial response (6%), two a minor response (4%) and 32 (64%) no change of disease. The median survival time was 8.5 months for all patients, the median time to progression of disease was 4.6 months and the 1-year survival rate was 28%. CLFT was fairly well tolerated. These data suggest that biochemical modulation of 24-hour infusional 5-FU with leucovorin together with cyclophosphamide and tamoxifen has some positive effects in the treatment of pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Prognosis; Survival Rate; Tamoxifen

Thirty-four patients with metastatic breast cancer (MBC) who had progression of disease after high-dose chemotherapy (HDCT) with peripheral blood progenitor cell support (PBPC) had methotrexate, uracil and tegafur (UFT), and leucovorin (MUL) therapy administered: methotrexate administered intramuscularly in combination with UFT given orally and leucovorin given orally. All patients had received extensive prior chemotherapy including a high-dose regimen with PBPC support. Two complete responses (CR) and 11 partial responses (PR) were observed (objective response rate: 13/34 or 38%, 95% confidence interval 22-56%). Seven additional patients had stable disease (SD), 4 of whom (12% of the total population) of 6 months or longer duration, with the clinical benefit rate (CR + PR + SD of at least 6-month duration) reaching 50%. Median follow-up was 38 months, and the median time to progression and the median overall survival time from the start of MUL were 5.5 and 11 months, respectively. Toxicity was mainly gastrointestinal. Eight patients (24%) had World Health Organization grade II or greater diarrhea and/or enteritis and, consequently, the UFT dose was reduced. Emesis was mild and easily manageable with thiethylperazine given orally. The regimen did not produce significant myelosuppression or alopecia. In conclusion, patients with MBC retain chemosensitivity even when they progress after HDCT/PBPC and can be treated again with chemotherapy. MUL is active and well tolerated in patients with MBC progressing after HDCT. Further studies with this regimen, as salvage chemotherapy or as maintenance chemotherapy after HDCT/PBPC, would appear to be warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leucovorin; Methotrexate; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Survival Analysis; Tegafur; Uracil

Chemotherapy has a limited impact on adenocarcinoma of the stomach. Although biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) and interferon-alpha (IFN-alpha) has improved the outcomes of patients with metastatic colorectal carcinoma compared with 5-FU alone, this approach has not been extensively evaluated in the treatment of advanced gastric carcinoma.. Twenty-seven patients with bidimensionally measurable, metastatic gastric carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 received the combination of IFN-alpha (5 million U/m2 administered subcutaneously daily on Days 1-7), LV (500 mg/m2 administered intravenously over 30 minutes immediately after IFN-alpha on Days 2-6), and 5-FU (370 mg/m2 given as an intravenous bolus 60 minutes after LV on Days 2-6), with treatment repeated every 4 weeks. Oral cryotherapy was administered routinely before each dose of 5-FU to reduce the incidence of severe stomatitis.. The median age of the patients was 58 years (range, 20-76), and 22 patients had residual, unresectable primary lesions. The median number of cycles received was 3 (range, 1-11). Of 24 patients who received at least 2 cycles of treatment, 15 (62.5%) did not require dose reduction for toxicity during the initial 2 cycles. The predominant toxicities were gastrointestinal: diarrhea and stomatitis of Grade 3-4 occurred in 28.6% and 35.7% of patients, respectively. Other severe (Grade 3-4) toxicities were granulocytopenia (which occurred in 21.4% of patients) and fatigue (in 10.7%). Fever and flu-like symptoms were common but usually mild. Of 24 patients who were evaluable for response, 3 had partial responses (PR) of 16, 23, and 33 weeks' duration, respectively, for a response rate of 12.5% (95% confidence interval = 2.7-32.4%). Two additional patients had reductions in tumor size sufficient for PR, but scans to document the minimum required response duration of 4 weeks were not obtained before progressive disease occurred. The median progression-free and overall survivals were 2.5 and 7.8 months, respectively.. Although this regimen can be administered safely with appropriate supportive care to patients with good performance status, it has limited therapeutic activity in patients with advanced gastric carcinoma.

Topics: Adult; Aged; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Stomach Neoplasms; Stomatitis; Treatment Outcome

To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity.. Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7).. Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response.. The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Remission Induction

The efficacy of combination therapy with vinorelbine, cyclophosphamide, and 5-fluorouracil was assessed in women who had received no prior therapy for locally advanced or metastatic breast cancer. Sixty patients with metastatic breast cancer who had finished any adjuvant therapy at least 6 months previously and who had not received treatment for advanced disease were entered onto the study. The schedule consisted of vinorelbine (Navelbine, Pierre Fabre Medicament) 25 mg/m2 on days 1 and 8, cyclophosphamide 500 mg/m2 on day 1, and 5-fluorouracil 500 mg/m2 followed by folinic acid 200 mg/m2 on days 1 and 8. Treatment was repeated every 21 days up to a maximum of 8 cycles. Objective responses were observed in 27 of 60 patients (45%; CI95 32.4-57.6) including 4 complete responses (6.7%; CI95 0-13) and 23 partial responses (38.3%; CI95 22.5-54.1). The responses were achieved in both visceral and nonvisceral sites and at the same rate for patients with multiple sites of disease. Neutropenia was dose limiting, with 40% of patients affected at grade 3 or 4, while other hematologic and nonhematologic toxicity was very mild. This schedule achieves good levels of response without the use of an anthracycline, so it is suitable either for patients who have been extensively exposed to anthracyclines during adjuvant therapy or for those who have other contraindications to their use.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Survival Analysis; Vinblastine; Vinorelbine

This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer.. Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Patients treated at the first dose level received vinorelbine 20 mg/m2 on day 1, doxorubicin 40 mg/m2 on day 1, methotrexate 100 mg/m2 on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The vinorelbine dose was escalated by 5 mg/m2 for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was then escalated by 10 mg/m2 with the vinorelbine dose held at its MTD.. total of 98 courses of treatment (median of 4 per patient, range 2-8) were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m2, doxorubicin 40 mg/m2, and methotrexate 100 mg/m2 with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were 3 complete responses (15%, 95% confidence interval 3%-38%), 5 partial responses (25%, 95% confidence interval 9%-49%) and an overall response rate of 40% (95% confidence interval 19%-64%). The median survival was estimated to be 25 months from the start of chemotherapy.. Vinorelbine at 25 mg/m2 can be safely administered with doxorubicin at 40 mg/m2 and methotrexate at 100 mg/m2 with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents may not be more effective than the combination of vinorelbine and doxorubicin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Doxorubicin; Female; Humans; Leucovorin; Methotrexate; Middle Aged; Neoplasm Metastasis; Vinblastine; Vinorelbine

In the authors' previous experience, the addition of epidoxorubicin to the FA-FU regimen obtained a better response rate than that of FA-FU alone in patients with advanced gastric cancer. Furthermore, considering the good efficacy and mild toxicity observed with the addition of etoposide to the FA-FU combination in the German study, the authors conducted a trial to explore the efficacy and tolerability of the ELFE regimen (epirubicin, folinic acid, fluorouracil, and etoposide) in previously untreated advanced gastric cancer patients. Of the 55 patients entered, 51 were evaluable for efficacy. Four complete responses (8%) and 21 partial responses (41%) were observed, with an overall response rate of 49% (95% CI: 35-63%). The median duration of response and survival were 6 and 8 months, respectively. Responder patients showed a significantly better median survival duration than nonresponders (12 vs. 4 months, respectively; p < 0.0001). Toxicity was evaluated in all patients: only 1 patient refused to continue therapy despite low toxicity. As expected, the major toxicities observed were gastrointestinal disturbance, leukopenia, and loss of hair. In conclusion, the ELFE combination regimen appears to be effective and well tolerated for the treatment of advanced gastric cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Epirubicin; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Stomach Neoplasms; Survival Analysis

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus +/- LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m2 per day and the l-LV dose being 5 mg/m2 per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3-4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8-25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus +/- LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin.

Topics: Adult; Aged; Camptothecin; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

This is a phase I dose-escalation study of uracil and tegafur (in a molar ratio of 4:1 [UFT]) administered in combination with calcium folinate and paclitaxel in metastatic breast cancer. This trial was initiated to 1) determine the maximum tolerated dose and dose-limiting toxicities of UFT plus calcium folinate (Orzel) administered three times per day for 21 days in combination with paclitaxel; and 2) define the appropriate dose for phase II testing. Thus far, 14 patients have been accrued to three dose levels. Two patients developed dose-limiting toxicities at dose level 3. One patient experienced grade 3 hypotension. A second patient experienced grade 3 vomiting, grade 4 diarrhea, and severe hand-foot syndrome. Two partial responses and one complete response have been observed. Early trends suggest that this regimen is active in metastatic breast cancer and is well tolerated. Completion of this study is anticipated in 1999.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Tegafur; Treatment Outcome; Uracil

This phase I study was designed to determine the maximum tolerated dose (MTD) and dose-limiting side effects of combination treatment with paclitaxel (Taxol) and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) for advanced metastatic breast cancer. After premedication, patients received paclitaxel as a 3-hour IV infusion (175 mg/m2) on day 1; UFT was administered orally at 300 mg/day (dose level 1), 400 mg/day (dose level 2), 500 mg/day (dose level 3), or 600 mg/day (dose level 4) in combination with 90 mg/day of calcium folinate in three divided doses for 14 days. Twenty patients with pretreated metastatic breast cancer have entered the trial so far. The main toxicity was neutropenia, occurring in 68% of patients. World Health Organization grades 1 and 2 peripheral neuropathy, arthralgia, and myalgia were common but not dose-limiting. All patients had grade 3 alopecia due to paclitaxel. One of six patients treated at dose level 4 experienced a dose-limiting toxicity with neutropenic fever. But within four dose levels MTD was not reached, and the study will continue to accrue patients to dose level 5. Objective responses were observed at all dose levels. In conclusion, the combination of paclitaxel and UFT plus oral calcium folinate seems to be a convenient and effective regimen for patients with pretreated metastatic breast cancer. Phase I is ongoing in order to determine MTD and the recommended dose for phase II testing.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Dexamethasone; Female; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Premedication; Tegafur; Treatment Outcome; Uracil

Paclitaxel (Taxol) is one of the most active drugs in the treatment of ovarian and breast cancers. Combination therapy with paclitaxel and 5-fluorouracil (5-FU) exhibits high activity in anthracycline-pretreated breast cancer, yielding response rates of 54% to 69% in recent studies. Weekly dosing of paclitaxel produces notable activity, while maintaining relatively low toxicity in heavily pretreated metastatic breast cancer patients. Uracil and tegafur (UFT) plus oral calcium folinate constitute an orally administered compound known as Orzel. This agent provides activity comparable to that of intravenously administered 5-FU plus calcium folinate, with the additional attributes of ease of administration and a more favorable side-effect profile. We initiated a phase I dose-finding trial to determine the maximum tolerated dose and dose-limiting toxicities of the combination of weekly paclitaxel by 1-hour infusion plus UFT/oral calcium folinate administered to patients with anthracycline-resistant metastatic breast cancer.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Leucovorin; Neoplasm Metastasis; Paclitaxel; Retrospective Studies; Tegafur; Treatment Outcome; Uracil

The combination of cisplatin and 5-fluorouracil (5-FU) (PF) is the most popular regimen for treating metastatic nasopharyngeal carcinoma (NPC) but it is limited by severe stomatitis and chronic cisplatin-related toxicity. A novel approach including induction with mitomycin C, doxorubicin and cisplatin (MAP) and subsequent maintenance with weekly 5-FU and leucovorin (FL) were designed with an aim to reduce acute and chronic toxicity of PF. Thirty-two patients of NPC with measurable metastatic lesions in the liver or lung were entered into this phase II trial. Mitomycin C 8 mg m(-2), doxorubicin 40 mg m(-2) and cisplatin 60 mg m(-2) were given on day 1 every 3 weeks as initial induction. After either four courses or remission was achieved, patients received weekly dose of 5-FU 450 mg m(-2) and leucovorin 30 mg m(-2) for maintenance until disease progression. With 105 courses of MAP given, 5% were accompanied by grade 3 and 0% were accompanied by grade 4 stomatitis. The dose-limiting toxicity of MAP was myelosuppression. Forty per cent of courses had grade 3 and 13% of courses had grade 4 leukopenia. No grade 3 or 4 cisplatin-related toxicity was observed. The overall response rate was 94% (95% confidence interval (CI) 84.9-100%) with a complete response rate (CR) of 6% (95% CI: 0-15.2%) and a good partial response (PR) rate of 28% (95% CI 11.7-44.6%), which was optionally defined as observance of only equivocal lesion identifiable under imaging study. Twenty-seven cases entered weekly FL maintenance phase. The median duration of maintenance with weekly FL was 38 weeks (8-91 weeks). There was no grade 3 or 4 toxicity noted during weekly FL. The median progression-free survival and overall survival were 11.6+/-0.4 and 18.1+/-3.6 months respectively. Six patients with a median follow-up of 19.8 months (9.6-41.0 months) were still alive and five of them had disease under control with FL. Good responders (CR and good PR) had better survival than less satisfactory responders (PR and stable disease) (P = 0.05). From Cox's multivariate regression analysis, the only significant prognostic factor for survival was good response to MAP (P = 0.042). Liver metastasis was the only significant variable in the best subset regression model that predicted good response to MAP (CR and good PR) (P = 0.027). MAP was an effective combination for metastatic NPC with minimal stomatitis and cisplatin-related toxicity but had significant myelosuppression. Weekly FL was a maintenance

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Doxorubicin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Staging; Survival Rate; Time Factors

The current treatment of advanced urothelial carcinoma generates high response rates but is associated with poor overall survival. The current study evaluated the efficacy and toxicity of a new combination of active drugs in the treatment of urothelial carcinoma.. Twenty-four patients with muscle invasive or metastatic urothelial carcinoma were enrolled. Fifteen patients (63%) had metastatic disease whereas 9 patients had T2-T4 disease. Three patients were unevaluable for response because of significant toxicity. Patients were treated every 28 days with methotrexate, 60 mg/m(2), intravenously (i.v.) on Day 1; cisplatin, 25 mg/m(2)/day, by continuous i.v. infusion on Days 2-6; 5-flurouracil (5-FU) 800 mg/m(2)/day by continuous i.v. infusion on Days 3-6; and leucovorin, 500 mg/m(2)/day, by continuous i.v. infusion on Days 2-6. Dosage in subsequent cycles was adjusted according to toxicity.. The median follow-up was 81 months (range, 53-97+ months). The overall response rate (complete response + partial response) for all 24 patients was 63% (95% confidence interval, 41-81%). The median survival was 65 months in the patients with muscle invasive disease and 17 months in the patients with metastatic disease. The duration of response in patients with metastatic disease was 6 months (range, 4-19 months). Toxicity was significant, with 82% of patients experiencing Common Toxicity Criteria Grade 3 or 4 neutropenia and 63% experiencing Grade 3 or 4 thrombocytopenia. However, only three patients developed febrile neutropenia and gastrointestinal and neurologic toxicity was moderate.. The combination of methotrexate, cisplatin, 5-fluorouracil, and leucovorin represents an active regimen in the treatment of urothelial carcinoma with a moderate toxicity profile. As new drugs are found to treat urothelial carcinoma, further studies will be needed to evaluate the role of traditional agents such as 5-fluorouracil and methotrexate in new combination chemotherapeutic regimens.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Female; Fluorouracil; Follow-Up Studies; Humans; Kidney Neoplasms; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Survival Rate; Urinary Bladder Neoplasms

Although combination chemotherapy regimens may prolong survival for selected patients with metastatic breast cancer, few, if any, are cured. The standard regimens used in treatment, e.g., CMF (cyclophosphamide, methotrexate, and fluorouracil [5-FU]), FAC (5-FU, Adriamycin, and cyclophosphamide), and FEC (5-FU, epirubicin, and cyclophosphamide), were developed over a decade ago. Current efforts to improve therapeutic efficacy have concentrated on decreasing drug toxicity and increasing drug doses (e.g., high-dose chemotherapy with peripheral stem-cell support). An important alternative approach to increasing therapeutic efficacy focuses on altering the administration schedules of well-known chemotherapeutic agents and introducing active new agents. One of the most frequently used cytotoxic drugs, fluorouracil (5-FU), has documented activity in a variety of malignancies, most notably, breast cancer and gastrointestinal tract cancers. However, despite broad clinical experience with 5-FU, our knowledge about the mechanisms of resistance to the various administration schedules used is limited. In vitro data and clinical experience show that resistance to one schedule of 5-FU can be overcome by using alternative schedules, in particular, a protracted infusion. This article discusses our clinical experience with weekly high-dose 24-hour infusions of 5-FU in combination with folinic acid (leucovorin) alone and together with paclitaxel (Taxol) for the treatment of advanced breast cancer.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Drug Therapy, Combination; Female; Fluorouracil; Forecasting; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel

From February 1995 through October 1996, 25 patients with metastatic colorectal cancer showing a clinical resistance to 5-fluorouracil (5-FU) entered this study. Thirteen received oxaliplatin alone and 12 received it in combination with 5-FU. Oxaliplatin was administered at 130 mg/m2 over a 2-hour infusion every 3 weeks, alone or added either to 5-FU as a continuous infusion at 200 mg/m2 to 300 mg/m2 (six patients) or to a 5-FU bolus, 375 mg/m2, plus leucovorin, 100 mg/m2, daily for 5 days every 3 weeks (6 patients). Eighty-six of 98 administered cycles were evaluable for toxicity (47 for oxaliplatin plus 5-FU and 39 for oxaliplatin alone). Hematologic toxicity was mild, occurring as grade 2 leukopenia in 23% of the cycles of 5-FU and oxaliplatin and in 5% of the cycles of oxaliplatin alone. The most common toxicity was neurologic (grade 1 to 2 in 60%-6% of the cycles of the combination, respectively, and 68%-10% of oxaliplatin given alone) as hand-foot paresthesia or hypersensitivity to cold. No grade 4 toxicity was reported and only three patients in the 5-FU group developed grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 33% of the cycles when both drugs were given and in 15% when oxaliplatin was administered alone. The combination of oxaliplatin and 5-FU induced four partial remissions (33%; 95% confidence interval, 6%-60%), whereas eight patients of the whole group had stable disease. No response occurred when oxaliplatin was administered as a single agent. The results of this study confirm the antitumor activity of oxaliplatin when added to 5-FU in patients who have metastatic colorectal cancer previously refractory to 5-FU. The possible therapeutic synergy with 5-FU was not accompanied by increased toxicity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Remission Induction

Patients with colorectal carcinoma progressing after a 5-fluorouracil (5-FU)-containing regimen were eligible. One treatment cycle consisted of repeated administrations of 5-FU combined to folinic acid for six times and to oxaliplatin for three times over 50 days. 5-FU was given at the dose of 2.6 g/m2 as a continuous infusion over 24 h on days 1, 8, 22, 29 and 43 preceded by i.v. folinic acid (FA) at a dose of 500 mg/m2 over 1 h. Oxaliplatin was given 1 h after 5-FU at the dose of 130 mg/m2 over a 2 h infusion on days 1, 22 and 43. A total of 37 patients were treated according to this schedule. The rates of objective responses after the first and second treatment cycles were 28 and 17%, respectively, with rates of tumor growth control, i.e. including the stabilizations, of 55 and 28%. The median duration of response was 10 months and the median duration of stabilizations was 6 months. The median survival time from initiation of oxaliplatin-containing therapy is 10 months (2-28+). The median survival time from the diagnosis of metastatic disease is 24 months (2-40+). The main toxicities were leucopenia, diarrhea, fatigue and paresthesias. The combination of 5-FU/FA/oxaliplatin was well tolerated and appears as a meaningful therapy after failure of a previous 5-FU-containing treatment.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Survival Analysis; Time Factors

Patients with advanced gastric cancer unresponsive or progressing after PELF chemotherapy (5-fluorouracil, leucovorin, cisplatin and epidoxorubicin) received paclitaxel at the dose of 225 mg/m2 every 3 weeks, over 3 h infusion. Thirty-six patients entered the study, and all of them were evaluable for response and toxicity. Toxicity was mild: apart from alopecia, grade 3 toxicities were leukopenia and thrombocytopenia in six patients, and grade 2 neurotoxicity in seven patients. Eight patients (22.2%, 95% CI: 9-35%) achieved an objective response, with a median duration of 5 months. Median survival time for all patients was 8 months. In 16 of 36 patients (44%), treatment determined a significant relief of symptoms. Out-patient paclitaxel given over 3 h may be effective as salvage treatment in patients with advanced gastric cancer refractory to first line chemotherapy.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Epirubicin; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Paclitaxel; Stomach Neoplasms; Survival Analysis; Thrombocytopenia; Time Factors

Ifosfamide-based chemotherapy has already been the basis of three separate clinical trials. In this study, ifosfamide was administered to lung cancer patients who had failed to respond to previous chemotherapy, to assess its response rate and toxicity.. From January 1993 to December 1996, 21 patients were treated, including eight patients with small cell lung cancer (SCLC) and 13 with non-small cell lung cancer (NSCLC). Patients who had histocytologically confirmed lung cancer, were previously treated with chemotherapy, had a measurable lesion(s), were younger than 75 years of age, had an Eastern Cooperative Oncology Group performance status of 0-3 and adequate marrow, renal and liver function were eligible for inclusion in this study. For SCLC patients, ifosfamide 2.4 g/m2 intravenous (i.v.) infusion was given over 30 minutes on days 1-3 every four weeks. For NSCLC two regimens were used: IFL (ifosfamide 2 g/m2, 5-fluorouracil (FU) 600 mg/m2 and leucovorin 50 mg/m2 i.v. infusion on days 1-3 every four weeks) and LIFE (leucovorin 50 mg/m2, ifosfamide 1 g/m2, 5-FU 400 mg/m2 and epirubicin 12 mg/m2 i.v. infusion on days 1-3 every four weeks). For NSCLC patients, IFL was used for the first two years of treatment and LIFE was used in the last two treatment years. All patients were evaluated for treatment response and toxicity.. The major toxic effect, myelosuppression (grade 3 or 4 leukopenia), occurred in 62.5% of SCLC patients and 23.1% of NSCLC patients during treatment, and in 62.5% and 10% of SCLC and NSCLC patients, respectively, throughout the course. Only one SCLC and one NSCLC patient experienced febrile neutropenia. One toxic death, attributed to febrile neutropenia, was documented in a patient with SCLC. Alopecia was ubiquitous. Other toxicities were uncommon and mild. The overall response rate was 50% in SCLC and 7.7% in NSCLC. The median time to disease progression was 61 days in SCLC and 47 days in NSCLC. Median survival was 172 days in SCLC and 173 days in NSCLC.. The study results suggest that ifosfamide chemotherapy is active with an acceptable toxicity profile in previously treated SCLC patients. However, it lacks efficacy in NSCLC patients who have been previously treated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Epirubicin; Female; Fluorouracil; Humans; Ifosfamide; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Salvage Therapy

Topics: Antibiotics, Antineoplastic; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Doxorubicin; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Stomach Neoplasms; Treatment Outcome

A phase II trial was performed to investigate the efficacy and tolerance of vinorelbine (VNB), 5-fluorouracil (5-FU), l-leucovorin (LLV) and recombinant human granulocyte colony-stimulating factor (G-CSF) in advanced breast cancer. Between August 1994 and October 1996, 53 patients entered this trial. Thirty-seven patients were previously untreated and 16 patients had failed previous palliative chemotherapy with (n = 12) or without anthracyclines (n = 4). Therapy consisted of VNB 40 mg m(-2) diluted in 250 ml of saline infused over 30 min on days 1 and 14 and LLV 100 mg m(-2) administered by intravenous bolus injection and 5-FU 400 mg m(-2) diluted in 500 ml of saline infused over 2 h, both given on days 1-5 every 4 weeks. G-CSF was administered at 5 microg kg(-1) day(-1) subcutaneously on days 6-10 during each cycle. Treatment was continued in cases of response or stable disease until a total of six courses were completed. The overall response rate was 59% for chemotherapeutically naive patients (95% confidence interval 42-75%), including five complete responses (CR; 13%) and 17 partial responses (PR; 46%); ten patients (27%) had stable disease (SD) and only five (14%) progressed (PD). Second-line chemotherapy with this regimen resulted in 3/16 (19%) objective remissions, but nine patients had SD and four had PD. The median time to progression was 10.5 months (range 2-23) in previously untreated patients and 7.0 months (range 2-19) in those who had failed prior chemotherapy. After a median follow-up time of 14 months, 29 patients (55%) are still alive with metastatic disease; median survival has not been reached yet. The dose-limiting toxicity was myelosuppression: WHO grade III and IV neutropenia occurred in 15 (28%) and four patients (8%), and was complicated by septicaemia in two; grade III anaemia and thrombocytopenia were noted in four (8%) and three (6%) patients respectively. Severe (WHO grade 3) non-haematological toxicities included stomatitis in 6% and nausea/vomiting and alopecia in 2% each. Our data suggest that the combination of vinorelbine, 5-fluorouracil and l-leucovorin plus G-CSF is an effective first line regimen for treatment of advanced breast cancer. Overall toxicity was modest, with myelosuppression being the dose-limiting side-effect. Other severe adverse reactions were uncommon.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Remission Induction; Survival Analysis; Vinblastine; Vinorelbine

Data from 12 metastatic colorectal cancer patients who were submitted to a pilot study with a multistep subcutaneous (sc) low dose recombinant interleukin-2 (rIL-2), 5-fluorouracil (5-FU) and leucovorin (LV) administration were compared with those from 13 historical controls who were comparable for the major prognostic indices. All 12 patients in the pilot study were subjected initially to six to eight courses of 5-FU-LV by endovenous (ev) bolus consistent with the Machover schedule alternating with 6 weeks of rIL-2 cycles. At the progression of metastatic disease, the patients were given 500 mg/m2 per day of 5-FU by continuous infusion (ci) for 5 days every 4 weeks and in case of further progression, 2,600 mg/m2 of 5-FU by 24-h ci once a week for 6 weeks. The control patients were treated with 5-FU-LV by the Machover schedule until progression and then observed. As yet, two patients in the pilot study and three control patients are currently alive. In the pilot study, the patients' response rate (CR + PR) and overall response rate (CR + PR + SD) were much higher than in the controls (50 vs 23% and 92 vs 54%, respectively). Time duration of response and survival from primary surgery were more prolonged in the pilot study than in the historical control, although not significantly (10.5 vs 6 and 41.5 vs 29 months, respectively). Time from starting therapy to progression and survival from relapse were significantly in favour of the pilot study (11.5 vs 4 and 31 vs 13.5 months; P < 0.01 and P < 0.05 unpaired t-test, respectively). Low dose s.c. rIL-2 cycles were well tolerated and no interruption occurred. In the pilot study sporadic grade 3 toxicity (diarrhoea or leucopenia) was responsible for the reduction of 5-FU doses to 80% of the previous infusion, but no treatment was postponed. In conclusion, these preliminary data suggest the opportunity to initiate large prospective randomized trials using a multistep therapy with rIL-2, 5-FU ci at conventional and at high dose in metastatic colorectal cancer.

Topics: Aged; Colonic Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Interleukin-2; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pilot Projects; Rectal Neoplasms; Survival Rate

This multicenter phase II study was designed to assess the efficacy of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer (CRC).. Patients with histologically proven metastatic colorectal cancer, and at least one bidimensionally measurable lesion, aged 18-70, with performance status < or = 2, normal baseline biological values and no prior chemotherapy (or only adjuvant chemotherapy completed > or = 6 months before study entry) were selected. Treatment was irinotecan 350 mg/m2, i.v., day 1, alternating with leucovorin 20 mg/m2 i.v. and 5-FU 425 mg/m2, i.v. daily for five consecutive days, day 22-26 (Mayo Clinic regimen). One alternating cycle was to be performed every six weeks. Patients were evaluated for efficacy every alternating cycle. Treatment was administered until five alternating cycles, disease progression, unacceptable toxicity or patient refusal.. Thirty-three patients (28 chemotherapy-naïve and five with prior adjuvant treatment completed > 1 year prior to accrual) were enrolled. The objective response rate (RR) was 30% (95% CI: 16-49; 10 patients/33; nine partial response and one complete response). All responses were reviewed by an independent external review committee. An additional 49% of patients had stable disease. The median survival was 16 months, the one year survival amounted to 58% and the median progression free survival was 7.2 months. Relative dose intensity was nearly 90% for both drugs. Grade 3-4 diarrhea and neutropenia were the most frequent severe toxic events, seen in 24% and 64% of patients, respectively.. The alternating schedule of CPT-11 350 mg/m2 with five days bolus of 5-FU and low dose LV is an active and feasible regimen as front-line therapy for metastatic CRC. It is well tolerated, without evidence of overlapping toxicity. The response rate appears promising with regard to that expected with either single agent. This regimen warrants further assessment in randomized trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Recombinant Proteins; Treatment Outcome

The activity and toxicity of UFT (Tegafur and Uracil) in a 4:1 molar concentration, plus leucovorin (LV), were evaluated in the treatment of 45 patients with advanced, bidimensionally measurable metastatic colorectal carcinoma. Initially 350 and later 300 mg/m2/day, plus 150 mg LV, as administered in divided doses every 8 h for 28 days. After two courses of treatment, responses were evaluated. The overall response rate was 42.2%, with responses observed in liver (n = 18), lung (n = 6), and bone (n = 1). Five of the 7 patients who received 350 mg/m2 UFT experienced prolonged grade 3 diarrhea, resulting in a dose reduction to 300 mg/m2; 9 patients in the 300-mg/m2 group experienced grade 3 diarrhea, vomiting, abdominal cramping, and fatigue. Minor toxic effects included oral mucositis and rash. The oral regimen of 300 mg/m2/day UFT, plus 150 mg/day LV, administered for 28 days appears to have significant activity against metastatic colorectal carcinoma. The treatment is well tolerated; neutropenia did not occur, and oral mucositis was not significant, even though both are characteristic of intravenous schedules of 5-fluorouracil plus LV. The results of this trial constitutes the basis of phase III clinical trials comparing this oral schedule with intravenous 5-FU and LV to compare clinical efficacy, impact on well-being, and cost. In addition, the current National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant colon clinical trial (CO-6) will compare this 28-day schedule of UFT plus oral leucovorin with a weekly regimen of intravenous 5-fluorouracil plus leucovorin in the postoperative adjuvant therapy of Dukes' B and C colon cancer patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Drug Combinations; Humans; Leucovorin; Neoplasm Metastasis; Survival Analysis; Tegafur; Uracil

5-Fluorouracil plus folinic acid and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic breast cancer patients. Paclitaxel and 5-fluorouracil have additive cytotoxicity in MCF-7 cell lines. We performed a phase II trial of paclitaxel 175 mg/m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before 5-fluorouracil 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic breast cancer. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 neutropenia requiring hospitalization; seven (4%) cycles in two patients required granulocyte colony-stimulating factor due to neutropenia; no patient required platelet transfusions. Grade 3/4 nonhematologic toxicities were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior doxorubicin exposure, 11 (58%) responded compared with nine of 15 (60%) without prior doxorubicin. Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Fatigue; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mucous Membrane; Neoplasm Metastasis; Nervous System Diseases; Paclitaxel

Based on reports of substantial antitumor efficacy of the combination of mitoxantrone (DHAD), 5-fluorouracil (FU) and leucovorin (LV), a clinical trial was performed to attempt augmentation of the dose of DHAD with filgrastim support. The doses and schedules, all intravenous, were DHAD (total dose divided over days 1 and 2), level I, 16 mg/m2; II, 20 mg/m2; III, 24 mg/m2; IV, 32 mg/m2; and LV, 300 mg, followed by FU, 350 mg/m2, on days 1-3. Filgrastim was given at 5 micrograms/kg/day subcutaneously on days 4-13. The planned cycle length was 21 days. Three or 4 patients were to be entered at each dose level and the maximum tolerated dose (MTD) was defined as the dose immediately below that which resulted in 2 patients with dose-limiting toxicity (DLT) in cycle 1. Once an apparent MTD was identified, an additional 6 patients were to be entered. Twenty patients (pts) were entered: level I: 3 pts; II: 3 pts; III: 10 pts: IV: 4 pts. The major toxicity was found to be cumulative thrombocytopenia with platelet counts < or = 20,000/microL occurring after cycle 1 at all levels beyond level I and five pts (25%) were removed from treatment solely because of platelet toxicity. Additional serious toxicities included grade 4 stomatitis in one patient (level IV) and cardiac toxicity in 2 patients with prior doxorubicin exposure. Ten pts had measurable and 8 had evaluable disease, and in 17 pts assessed, 5 (29%) achieved an objective response. The response rates in this study are lower than reported in the literature for the combination of DHAD, 5FU, LV and this may be related to the fact that only 40% of the patients were removed from protocol treatment because of disease progression. On the basis of limited DHAD-dose augmentation, toxicities observed, and modest response rate, the filgrastim-supported DHAD, 5FU, LV regimen as utilized in this study cannot be recommended for further development for treatment of women with metastatic breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Filgrastim; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Leukopenia; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Patient Selection; Platelet Count; Recombinant Proteins; Survival Rate; Thrombocytopenia; Time Factors

Experimental studies have demonstrated that 5-fluorouracil (5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity. Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZT is 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU + l-leucovorin (LV), and that this combination has promising antitumor activity. The purpose of this study was therefore to evaluate the antitumor activity of weekly bolus 5-FU + LV + AZT, administered at its MTD, and to determine whether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells.. Twenty-nine chemotherapy-naïve metastatic colorectal cancer patients with measurable disease entered the study to evaluate the activity of a weekly 5-FU 500 mg/m2 i.v. bolus + LV 250 mg/m2 i.v. two-hour infusion + AZT 8000 mg/m2 i.v. two-hour infusion. In 10 different patients, who during three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNA strand breaks in blood nuclear cells were determined by a fluorescent analysis of DNA unwinding.. Treatment was generally well tolerated and WHO grades III-IV toxicities, consisting mostly of diarrhea (17%), were uncommon. One patient died of severe diarrhea with consequent hypokalemia and cardiac arrhythmia. All patients were considered evaluable for response, and 3 (10%) complete and 10 (35%) partial responses were observed, for an objective response rate of 45% (95% confidence limit interval 26%-64%). Both 5-FU + LV and AZT decreased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FU + LV + AZT, which reduced the percentage of double stranded DNA to 50% and 36% after 24 and 48 hours, respectively, and this interaction between 5-FU + LV and AZT was found to be cumulative.. These studies demonstrate that the present dose and schedule of AZT in combination with 5-FU + LV has significant activity in metastatic colorectal cancer and that the combination of 5-FU + LV with AZT increases the amount of DNA damage. Therefore, AZT in combination with 5-FU + LV warrants further study in colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; DNA Damage; DNA, Neoplasm; DNA, Single-Stranded; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Injections, Intravenous; Leucovorin; Leukocytes, Mononuclear; Male; Middle Aged; Neoplasm Metastasis; Zidovudine

Fifty-five women with metastatic breast cancer were treated with a regimen consisting of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 175 mg/m2 administered intravenously over 3 hours on day 1 only plus leucovorin given intravenously over 30 to 60 minutes followed by 5-fluorouracil 350 mg/m2 via intravenous push on days 1 to 3 every 28 days for six cycles. Eight patients were chemotherapy naive. Of 47 previously treated women, 30 had received anthracyclines. Fifty-two patients were evaluable for response. Three (6%) experienced a complete response and 24 (46%) had a partial response, for an overall response rate of 52%. Patients previously exposed to doxorubicin had a response rate similar to those with no prior doxorubicin exposure (50% v 54%, respectively). The median duration of response was 8.6 months and median survival was 17.7 months. Toxicity was modest, with grade 3 or 4 neutropenia observed in only 5.5% (15 of 274) of cycles. Preliminary results indicate that paclitaxel/5-fluorouracillleucovorin is an active, well-tolerated regimen for treating metastatic breast cancer.

Topics: Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Survival Rate

Vinorelbine, is an active drug in the treatment of metastatic breast cancer and has a favorable toxicity profile. Its combination with other effective and well-tolerated cytotoxics may thus be beneficial. We investigated the therapeutic effect of a combination of vinorelbine plus 5-fluorouracil and folinic acid as first-line treatment in patients with metastatic breast cancer.. Forty-five patients with advanced or metastatic breast cancer were enrolled in this phase I-II study and treated with 5-fluorouracil (350 mg/m2 i.v. on day 1 to 3), folinic acid (100 mg/m2 i.v. on day 1 to 3) and vinorelbine given on days 1 and 3 at the dose of 25 mg/m2 (dose level 1), or 30 mg/m2 (dose level 2). Therapy was given on an outpatient basis every three weeks.. Phase I: Dose limiting toxicity (DLT) occurred at the second dose level of vinorelbine (30 mg/m2), with two out of three patients developing severe constipation ('ileus-like syndrome' grade 4), and fever (grade 2). Consequently, the dose evaluated in the phase II study was 25 mg/m2. Phase II: Objective responses were observed in 24 of 39 evaluable patients (95% confidence interval (95% CI), 47% to 77%). There were seven complete responses (18%), 17 partial responses (44%), and for nine patients (23%) disease was stable. Only six patients (15%) experienced disease progression. The median response duration was 10 months (range 6 to 24+) and the median time to progression was eight months (range 2 to 24+). Granulocytopenia was the most frequently observed side effect, with a grade 4 nadir being observed in 30 patients (77%), with four hospital admissions due to febrile neutropenia. Nausea, vomiting, and anorexia were mild to moderate and reported by less than half of the patients. Alopecia was moderate and occurred in about one-third of the patients. The other side effects were mild and easily manageable.. This effective combination chemotherapy of vinorelbine, 5-fluorouracil and folinic acid is comparable to other first-line regimens in terms of efficacy, and is subjectively well tolerated, thus deserving a test in randomized trials in the advanced and adjuvant settings.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Vinblastine; Vinorelbine

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil (5-FU)/leucovorin (LV) in intensively pretreated patients with metastatic breast cancer prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to the regimen for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin to the regimen for first-line treatment. Twenty-eight patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with high-dose 5-FU 2 g/m2 (24-hour infusion) plus LV 500 mg/m2 (2-hour infusion before 5-FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 before high-dose 5-FU/LV, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems (SIMS Deltec Inc, St Paul, MN) and portable pumps. Neutropenia was common but mild to moderate and of short duration in most patients. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle with mild to moderate expression. In 28 patients with bidimensionally measurable disease, 25% (seven of 28) attained a complete response, 57% (16 of 28) achieved a partial response, 11% (three of 28) had stable disease, and 7% (two of 28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). We conclude that the combination of paclitaxel/cisplatin with weekly high-dose infusional 5-FU/LV appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Remission Induction

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. We added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, 5-fluorouracil, and high-dose leucovorin. Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous infusion on day 1; mitoxantrone 10 mg/m2 by intravenous bolus on day 1; 5-fluorouracil 350 mg/m2 by intravenous bolus on days 1, 2, and 3; and leucovorin 300 mg intravenous over 30 to 60 minutes, immediately preceding 5-fluorouracil on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. Of 45 assessable patients, 23 (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. There were four treatment-related deaths, two sepsis, one congestive heart failure, and one sepsis and congestive heart failure, the last two after a large cumulative anthracycline dose. This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although how its activity compares with that of other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than had been anticipated based on previous results with the mitoxantrone/5-fluorouracil/high-dose leucovorin regimen or with single-agent paclitaxel administered at this dose and schedule. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with paclitaxel/doxorubicin combinations. We have embarked on a phase I/II trial of paclitaxel/mitoxantrone and have determined the maximum tolerated dose to be 200 mg/m2 and 10 mg/m2, respectively, without the use of cytokines. Fifteen patients have been treated at the maximum tolerated dose, and it is too early to assess results.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Mitoxantrone; Neoplasm Metastasis; Paclitaxel

In this phase II trial we have evaluated the activity and toxicity of a combination regimen containing mitoxantrone, L-leucovorin, and fluorouracil in patients with advanced breast cancer pretreated with anthracyclines. Forty-six patients were included into the study; they received a total of 227 cycles of chemotherapy. Median age was 63 years (range 34-78), median performance status was 80 (range 60-100). Visceral metastases were present in 37 patients, 6 patients had bone involvement only, while 3 patients had soft tissue/lymph node disease. Median number of previous chemotherapy regimens for advanced disease was 2 (range 1-3). Ten patients had anthracycline primary resistance (progressive disease during treatment). Twenty-three patients received mitoxantrone 12 mg/sqm day 1; fluorouracil 370 mg/sqm and L-folinic acid 100 mg/sqm days 1-3 administered every three weeks. Another group of 23 patients were treated with the same regimen using a prolonged 5FU/L-FA schedule (5 days). Two complete responses and 6 partial responses were recorded with the 3-day schedule; 7 partial responses in the 5-day schedule (overall response rate 32.6%, 95% C.I. 19-46%). Two partial responses were observed in patients with anthracycline primary resistance. Median response duration was 9 months (range 3-16). Hematologic toxicity was mild: grade 3-4 leukopenia was recorded in 5 patients, grade 3-4 thrombocytopenia in 3 patients. Grade III-IV stomatitis and diarrhea was recorded in 4 and 5 patients respectively (all receiving the 5-day 5-FU/L-FA schedule). Cardiac toxicity was observed in two cases. This regimen proved active in advanced breast cancer following anthracycline-containing chemotherapy, and the 3-day schedule could be offered to such patients with acceptable toxicity.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Breast Neoplasms, Male; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitoxantrone; Neoplasm Metastasis

Preliminary studies suggest synergy between oxaliplatin and fluorouracil (5-FU). To assess this issue, we performed a study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. Regimen consisted of oxaliplatin day 1, 130 mg/m2 every two cycles (folfox 1) or 100 mg/m2/cycle (folfox 2) or 85 mg/m2/cycle (folfox 3) and leucovorin 500 mg/m2 as a 2-hour infusion, followed by 5-FU 22 h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. One hundred and thirteen patients have been treated. One complete response (CR) and 32 partial responses (PRs) were observed for an overall response rate of 29.2%. Sixty-seven patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU than the one used in the folfox regimens, among them 18 had PRs (26.9%). The best response rate was observed in patients treated with the folfox 2 regimen: 41.7%. From start of folfox, median progression-free survival was 6 months and median survival 13 months. Limiting toxicities were peripheral neuropathy and neutropenia. Fifty-four percent of the patients experienced WHO toxicity > or = grade 3 with the folfox1 regimen, 45% with the folfox2 and 40% with the folfox3. The folfox regimens achieve a high response rate in pretreated patients with CRC. Further studies are needed to determine the best oxaliplatin dose-intensity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

We performed a Phase II trial of oral leucovorin and high-dose fluorouracil (5FU) in hormone refractory patients with metastatic prostate cancer who had not had prior chemotherapy. 5FU was given as a 24-hour infusion at a dosage of 4 g/m2 and oral leucovorin at a dosage of 50 mg every 6 hours for four doses, starting with the infusion of 5FU. Fifteen patients were treated and three were not evaluable for response. There were no complete (CR) or partial responses (PR) in 12 evaluable patients (95% confidence interval for CR+PR of 0 to 26%). Three patients had stable disease and the remainder progressed. Toxicities were generally mild to moderate, but one patient died of sepsis while neutropenic. This dose and schedule of leucovorin and 5FU is not better than single-agent 5FU in patients with metastatic prostate cancer.

Topics: Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Survival Analysis

We undertook a multicenter phase II trial of 5-fluorouracil (5FU) + 1-leucovorin (1-LV) in previously untreated patients with metastatic colorectal cancer to determine the response rate, response duration, time to progression, survival, and toxicity. Patients were treated with i.v. 5FU 370 mg/m2/day and 1-LV 100 mg/m2/day x 5 every 28 days. Toxicity and response were determined by WHO criteria. One hundred and twenty-six patients were entered, and 119 patients were eligible and evaluable. Eighty-eight patients had colon cancer and 37 had rectal cancer. The male:female ratio was 58:68. The mean age was 62.2 years. ECOG performance status distribution was 0 (39.7%), 1 (46%), and 2 (11.9%). The median number of courses of therapy administered was 4.5. Severe- or life-threatening stomatitis or diarrhea, nausea, and granulocytopenia occurred in 17.6, 23.2, 17.6, and 15.9% of patients, respectively. The response rate was 22/119 [18.5%; 95% confidence interval (CI) of 12.0-26.6]. Median response duration was 188 days (95% CI of 111-248 days). Median survival was 379 days (95% confidence interval of 289-452 days). These results indicate that when 1-LV is combined with 5FU, toxicity is similar in pattern and severity to that of the d,1 racemic mixture. The overall efficacy of 1-LV + 5FU is comparable to a recent metaanalysis.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Stereoisomerism; Survival Analysis

The purpose of this study was to test the hypothesis that 5-methyltetrahydrofolate (Me-THF), a source of reduced folates alternative to leucovorin, could effectively modulate 5-fluorouracil's (5-FU) cytotoxic activity in patients with advanced colon cancer. A total of 23 patients were enrolled in a phase 11 trial; they received 5-FU as a 30-min infusion at a dose of 370 mg/m2 following a rapid i.v. push of 200 mg/m2 Me-THF, both drugs being given for 5 consecutive days. Cycles were repeated every 4 weeks until disease progression. No patient achieved a complete response. In all, 4 patients showed a partial response (17.4%), 7 developed stable disease (30.4%), and the remaining 12 (52.2%) progressed. Toxicity was acceptable and never exceeded WHO grade III intensity. According to our experience, the MeTHF/5-FU combination does not appear to be an effective treatment for advanced colon cancer. Despite its low toxic profile, in our opinion its wider use should be discouraged.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Death; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Tetrahydrofolates

To compare sequential methotrexate (M) and fluorouracil (F) (M-->F) with surgery (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-13) and cyclophosphamide (C), M, and F with M-->F (NSABP B-19), in patients with estrogen receptor (ER)-negative tumors and negative axillary nodes.. A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility requirements were randomized to B-19. Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life-table estimates.. A significant benefit in overall DFS (74% v 59%; P < .001) was demonstrated at 8 years in all B-13 patients who received M-->F (69% v 56% [P = .006] in those or= 50 years). A survival advantage was evident in older patients (89% v 80%; P = .03). In B-19, through 5 years, an overall DFS advantage (82% v 73%; P < .001) and a borderline survival advantage (88% v 85%; P = .06) were evident with CMF. The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from CMF were greater in women aged F or CMF after lumpectomy and breast irradiation resulted in a low probability of ipsilateral breast tumor recurrence (IBTR). In B-13, the frequency of IBTR was 2.6% following M-->F versus 13.4% in women treated by lumpectomy; it was 0.6% following CMF in B-19. Toxicity >or= grade 3 was more frequent among CMF patients in B-19. The age-related difference in CMF benefit was not related to amount of drug received.. M-->F and CMF are effective for node-negative patients with ER-negative tumors. The incidence of local-regional or distant metastases and IBTR decreased after either therapy. The benefit from either therapy was evident in all patients, but the CMF advantage was greater in those F may be used in patients with medical problems that would preclude CMF administration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Mastectomy; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Receptors, Estrogen; Survival Rate

To determine the most effective dose of leucovorin (folinic acid [FA]) within a weekly bolus fluorouracil (FU) schedule, we conducted a randomized multicenter trial to compare therapeutic effects and toxicity of high-dose FA versus low-dose FA combined with FU at equal doses in both treatment groups.. Patients with measurable inoperable or metastatic colorectal cancer were randomized to receive weekly FU 500 mg/m2 by intravenous (IV) bolus combined with high-dose FA 500 mg/m2 (group A) or low-dose FA 20 mg/m2 (group B) by 2-hour infusion.. Of 291 assessable patients (group A, n = 148; group B, n = 143), we observed, in group A, complete response (CR)/partial response (PR) in 32 (21.6%), no change (NC) in 64 (43.2%), and progressive disease (PD) in 52 (35.1%); and in group B, CR/PR in 25 (17.5%), NC in 63 (44.1%), and PD in 55 (38.5%). The median response duration was 24.8 weeks in group A and 23.1 weeks in group B. Median progression-free intervals were 29.3 weeks (group A) and 30 weeks (group B). The median survival time was 55.1 weeks in group A and 54.1 weeks in group B. Overall toxicity was moderate. Mild nausea and vomiting, and stomatitis were common side effects in both groups. The incidence of World Health Organization (WHO) grade III/IV diarrhea was significantly higher in group A (40 v 23 patients). Severe side effects were observed only in a minority of patients in both arms. WHO grade IV diarrhea was observed in seven patients: four in group A and three in group B. The rate of toxicity-related adjustments of dose and schedule was comparable in both groups.. High-dose FA/FU is not superior to low-dose FA/FU within a weekly treatment schedule. Response rates and survival were comparable in both treatment arms. Treatment-related toxicity was higher in group A (high-dose FA). Therefore, low-dose FA combined with weekly FU may be considered the preferred treatment for metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Germany; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Palliative Care; Remission Induction; Survival Rate

From January 1992 to July 1993, 28 patients with metastatic breast cancer were entered in a phase II trial to assess the activity and toxicity of the combination of mitoxantrone, 5-fluoruracil, and leucovorin. Patients were eligible if they had progressive disease after either adjuvant (2 patients) or previous chemotherapy for metastatic disease (26 patients). Twenty-five patients (89.2%) had received previous anthracycline-based therapy. Predominant site of metastatic disease was visceral in 22 patients, bone in 2 patients, soft tissue in 4 patients, and the majority of patients (89.2%) had two or more sites of disease. The regimen was administered according to the following schedule: Mitoxantrone 9-12 mg/m2 i.v. on day 1; L-Leucovorin 150 mg i.v. over 1 hour before 5-Fluorouracil 350 mg/m2 i.v. push days, 1, 2 and 3. Courses were repeated every 21 days. Twenty-six patients were evaluable for response. We observed 2 complete responses, 5 partial responses with a median duration of 38 weeks (range 23-68). The objective response rate was 27% (95% C.I., 10% to 44%). Myelo-suppression was the most frequent toxicity, but it was mild in the majority of patients. Nine episodes of fever and neutropenia occurred in six patients but none of these episodes was fatal. No clinical evidence of cardiotoxicity was observed. At a median follow-up of 78 weeks, the median time to progression was 20.5 weeks and the median overall survival was 48 weeks. We conclude that this regimen is well tolerated and in our experience the objective response rate is similar to other salvage chemotherapy regimens.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Salvage Therapy

We have carried out a phase II trial to evaluate the efficacy and toxicity of a combination therapy consisting of mitoxantrone 10 mg/sqm i.v. on day 1, levo-leucovorin 250 mg/sqm administered over 2 hours and 5-fluorouracil 500 mg/sqm i.v. push after the first hour of levo-leucovorin infusion, on days 15-16 (MFL) in patients aged more than 65 years. 24 patients with advanced breast cancer entered the study: 16 aged 65-70 yrs, 4 patients 70-75 yrs, and 4 > 75 yrs. Median PS was 1 (range 0-2); sites of metastases were: bone 14 patients, viscera 14 patients, soft tissue 11 patients, and CNS 1 patient. A median number of 6 cycles (range 3-9) was administered. All patients were evaluable for response and toxicity; partial response was obtained in 12 (50%) patients (95% C.I 30-70), stable disease was observed in 9 patients (37.5%), while 3 patients (12.5%) progressed. Median progression-free survival and survival were 9 months (range 2-14) and 14 months (range 5-36), respectively. Toxicity was generally mild and the most frequently observed side-effects were WHO gr. 1-2 leukopenia in 6/24 (25%) patients and gr. 1-2 emesis in 10/24 (41.6%) pts. 1 patient pretreated with doxorubicin cumulative dose of 240 mg/sqm showed clinical signs of congestive heart failure (NYHA grade 1) after the fifth cycle of treatment. MFL is a well tolerated regimen and could represent a safe and effective treatment in older advanced breast cancer patients.

Topics: Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Mitoxantrone; Neoplasm Metastasis; Retrospective Studies; Treatment Outcome

Thirty-three consecutive patients with recurrent and/or metastatic colorectal carcinoma (CRC) refractory to previous chemotherapy have been treated with levofolinic acid (I-FA) 100 mg/m2 i.v. over 1 h infusion followed by 5-fluorouracil (5-FU) 600 mg/m2 i.v. bolus every week for 6 weeks followed by a 2 week interval. Patients also received rIL-2 s.c. at 3 MU daily from day 1 to day 5 of each week for at least four consecutive weeks per cycle. Enrolled patients were divided in two groups: (i) group 1 including patients with progressive tumor refractory to chemotherapy with I-FA + 5-FU given for metastatic disease and (ii) group 2 consisting of patients with diagnosis of metastatic disease within 3 months from the completion of adjuvant chemotherapy with 5-FU + levamisole (LEV) after primary surgery. No objective response was observed in the group of 11 patients with CRC resistant to previous I-FA + 5-FU, thus no further patient with progressive disease after I-FA + 5-FU was included in the trial. In the group of patients pretreated with 5-FU + LEV, four patients experienced a PR with a mean duration of 7.3 months (range > or = 4.0-8.6) for an overall response rate of 18% (95% CI 12-26%). A stabilization of disease was observed in five cases (23%) with a mean duration of > or = 5.6 months (range > or = 2.0-7.0). The remaining 13 patients progressed. No complete responses were achieved. The mean overall survival was > or = 9.5 months (range > or = 2.0-14.0). Toxicity was generally mild. This study demonstrates that the combination of s.c. rIL-2 and intravenous 5-FU + I-FA on a weekly schedule may be safely given to patients with metastatic CRC on an outpatients basis. The addition of low-dose rIL-2 does not modify the toxicity profile of 5-FU + I-FA, even if IL-2-related side-effects such as systemic symptoms or cardiac abnormalities are to be expected. The clinical activity of the combination is not good, at least in terms of response rate, even if the duration of partial responses may suggest to test rIL-2 in a prospective study with response duration and overall survival as the final end-points.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Injections, Subcutaneous; Interleukin-2; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Salvage Therapy

Many patients with advanced transitional cell carcinoma are unable to receive cisplatin-based therapy. The efficacy and toxicity of a carboplatin-based regimen in the treatment of patients with advanced transitional cell carcinoma was therefore evaluated.. Twenty-three patients with advanced transitional cell carcinoma were treated. Metastatic disease was present in 19 of 23 patients (83%) whereas 4 patients with T4, and/or N1, disease were treated. Patients were treated every 28 days with methotrexate, 30 mg/m2 intravenously (i.v.) on Days 1 and 15, along with leucovorin, 15 mg/m2 orally every 6 hours, 3 times daily beginning 24 hours after each methotrexate dose; vinblastine, 3 mg/m2 i.v. on Days 1 and 15; mitoxantrone, 15 mg/m2 i.v. on Day 1; and carboplatin, 300 mg/m2 i.v. on Day 1, adjusted for creatinine clearance (MVNCa). Dosage in subsequent cycles was adjusted according to hematologic toxicity.. Median age was 70 years (range, 52-83 years) and median pretreatment creatinine clearance was 50 mL/min (range, 30-106 mL/min). Of 23 patients, 8 (34.8%) obtained a complete response, and 5 (21.7%) obtained a partial response. The overall response proportion was 56.5% (95% confidence interval, 34.5-76.8%). Median survival was 10 months (range, 1-44+ months). Toxicity was moderate. Grade 4 neutropenia occurred in 10 of 107 (9.3%) administered treatment cycles; Grade 4 thrombocytopenia occurred in 11 of 107, (10.3%). There were 4 episodes of febrile neutropenia (3.7% of cycles). Renal, neurologic, or otic toxicity were not observed. Age older than 70 did not appear to impact on response proportion, survival, and toxicity.. The carboplatin-based MVNCa regimen is active in the treatment of patients with advanced transitional cell carcinoma and is well tolerated. Therapy with this regimen may be a less toxic alternative for patients for whom treatment with cisplatin is not an option.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Transitional Cell; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Survival Rate; Urinary Bladder Neoplasms; Vinblastine

In a previous phase I-II trial we showed that the maximum tolerable dose (MTD) of 5-fluorouracil (5-FU) in a weekly 48-hour continuous infusion (CI) was 3.5 g/m2. In a subsequent confirmative phase II trial with 85 evaluable patients, a 38.5% response rate was obtained, and a median survival of 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. On this basis we attempted to modulate high-dose 5-FU (3 g/m2) with oral leucovorin (LV) but the regimen was too toxic and the dose had to be reduced. A new phase II trial with 2 g/m2/week plus oral leucovorin was planned.. From July 1992 to June 1994, 110 previously untreated patients with advanced, measurable colorectal cancer were included in a multicenter study. The patients received, on an outpatient basis, 5-FU 2 g/m2 by continuous infusion for 48 hours once a week until progression or the appearance of toxic effects. Oral leucovorin (60 mg every six hours) was also given during the 5-FU infusion.. Patients received a median dose intensity of 5-FU of 1.6 g/m2/week (range 0.9-2). Three complete responses and 36 partial responses were observed. The overall response rate was 37.5% (95% CI, 28% to 46.8%), the median time to progression 7.4 months and median survival 14.5 months. W.H.O. grade 3 diarrhea occurred in 27 patients (24.5%); grade 3 mucositis was observed in 9 (8.1%) patients and grade 4 in one. Grade 3 nausea and vomiting was reported in 13 (11.7%) patients, while grade 3 hand-foot syndrome was detected in only 5 (4.5%). Grade 4 leukopenia occurred in one patient and grade 3-4 thrombocytopenia in two.. Oral leucovorin modulation of weekly 48-hour continuous infusion of 5-FU at 2 g/m2 is an active regimen, with diarrhea and mucositis as the main limiting toxic effects. Its antitumor activity does not seem superior to that obtained with a weekly 48-hour continuous infusion of 5-FU alone at a dose of 3.5 g/m2.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil (5-FU)/folinic acid (FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/ II outpatient study. Patients were treated with high-dose 5-FU (by 24-hour infusion) and FA (by 2-hour infusion prior to 5-FU) weekly for 6 weeks (day 1, 8, 15, 22, 29, and 36) repeated every 50 days; in addition, paclitaxel was administered by 3-hour infusion on days 1 and 22. The following dose levels were used in phase 1 of the study. In dose levels 1 through 4, FA was given at a fixed dose of 500 mg/m2, followed by escalating doses of high-dose 5-FU (24-hour infusions of 1.5 [dose level 1], 1.8 [dose level 2], and 2.0 g/m2 [dose levels 3 and 4]). The paclitaxel dose, given over 3 hours on days 1 and 22, was 135 mg/m2 for dose levels 1 through 3 and 175 mg/m2 at dose level 4. Dose level 4 was chosen for further evaluation in the phase II portion of the trial. Among the 46 patients who entered this part of the trial, the median age was 46 years (age range, 26 to 70 years), the World Health Organization performance status was 0 to 1, and the median number of metastatic sites was 2.5 (range, one to four). All patients had bidimensionally measurable disease. Nine patients previously had received adjuvant chemotherapy, 16 had received prior chemotherapy for metastasis, and 21 had been treated with both types of chemotherapy. Of 29 anthracycline-pretreated patients, 25 had anthracycline-resistant disease. Interim results in 35 evaluable patients show complete remission in one patient (3%), partial remissions in 18 (51%), stable disease in 14 (40%), and progressive disease in two (6%). The overall response rate was 54% (95% confidence interval, 36% to 76%). The median number of treatment cycles administered per patient was three (range, one to five), the median time to maximum response was 2 months (range, 1 to 5 months), and the median remission duration was 8+ months (range, 2 to 17 months). Median survival time has not yet been reached. The combination of paclitaxel with weekly high-dose 5-FU/FA was well tolerated in second-line treatment of metastatic breast cancer and results also indicate high efficacy against anthracycline-resistant disease. In an ongoing phase II study we are evaluating the addition of cisplatin to the regimen as f

Topics: Adult; Aged; Ambulatory Care; Antibiotics, Antineoplastic; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cisplatin; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Remission Induction; Survival Rate

This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP).. Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2.. World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively.. This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

The modulation of 5-fluorouracil (5-FU) with folinic acid (leucovorin, LV) is more efficacious than 5-FU alone in the treatment of metastatic colorectal cancer, and the combination of 5-FU with cisplatin is currently one of the most active regimens in advanced gastric cancer. A phase II study was therefore conducted to test the efficacy and toxicity of the combination of 5-FU, LV and cisplatin (FLP) in metastatic gastric cancer. 28 patients entered the study. Metastatic sites were observed in the liver (in 21 patients), the peritoneum (in 8), the lymph nodes (in 7) or the bones (in 1) and a local recurrence was noted in 4 cases. The performance status (using World Health Organisation criteria) was 0 for 13 patients and 1 or 2 for the others. Cycles of treatment were administered every 28 days and consisted of LV 200 mg/m2/day for 5 days followed by 5-FU 400 mg/m2/day for 5 days with cisplatin 100 mg/m2 on day 2. The response rate for the 27 evaluable patients was 51.8% (95% confidence interval (CI), 33-70.6%). There were four complete responses (14.8%) and 10 partial responses (37%). Median survival was 11 months and 4 patients were alive at 2 years. Both response rate and survival were better for patients with a good performance status. The overall toxicity was very low, except for 1 patient who died of dehydration and cardiac failure. In conclusion, the FLP protocol was effective and well tolerated in patients with metastatic gastric cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies; Stomach Neoplasms; Survival Rate; Treatment Outcome

In metastatic breast cancer patients who have had prior exposure to anthracyclines, single agents induce less than 15% and combination chemotherapy less than 20%-30% of objective responses. Therefore more active and tolerable salvage regimens are needed.. Forty-three patients with advanced breast cancer pretreated with 1-5 (median 2) different chemotherapy regimens were entered into this phase I/II trial. Treatment consisted of folinic acid (FA) (500 mg/m2, i.v., 2-hour infusion) followed by a 24-hour infusion of 5-fluorouracil (FU) which was escalated from 1.5 g/m2 (dose level (dl 1)), to 1.8 g/m2 (dl 2) to 2.1 g/m2 (dl 3). Therapy was given as outpatient treatment once weekly times 6 followed by a 2-week rest.. HD-FU/FA was well tolerated. No dose-limiting toxicity occurred at dl 1 or 2. Only 3/32 (9%) patients had WHO grade 3/4 toxicities (gastrointestinal toxicities, hand-foot-syndrome) at dl 3. The response rate for all 32 of the patients treated at dl 3 was 41% (13/32). In the 24 patients with anthracycline-refractory disease, a response rate of 41% (10/24) was achieved. The median remission duration was 11 months and the median survival time 19 months.. This schedule of FU/FA is a safe outpatient treatment with substantial activity in intensively pretreated breast cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Middle Aged; Neoplasm Metastasis; Pilot Projects

Advanced breast cancer remains a major clinical problem. Current chemotherapy regimens are able to induce a clinical response in many patients but do not appear to influence significantly patients' survival. The use of new drugs such as mitoxantrone with a predicted lower toxicity and biochemical modulation of 5-fluorouracil with levo-folinate are extensively studied research areas that could combine good therapeutic efficacy with the maintenance of an acceptable quality of life. 34 patients with advanced breast carcinoma were included in the study. Only 4 women had received prior chemotherapy for advanced disease. Treatment plan was: 5-fluorouracil 400 mg/m2 + l-leucovorin 100 mg/m2 days 1-3, cyclophosphamide 600 mg/m2 and mitoxantrone 12-14 mg/m2 on day 3, q28. G-CSF (5 micrograms/kg/d days 7-14) was routinely delivered to the patients with the aim of maintaining dose intensity. 15 patients obtained a response for an overall response rate of 44%. Mean duration was 10.2+ and 11+ months for complete and partial responses respectively. Mean overall survival was 14.4+ months. A high complete response rate was seen in liver metastasis (44%), while lung lesions had a lower probability of response (25%). Toxicity was globally mild with 23% of grade 3 vomiting and 15% of grade 3-4 leukopenia. Two cases of cardiotoxicity were reported. No difference in response rate or toxicity was identified between patients receiving two different mitoxantrone doses (12 or 14 mg/m2). The schedule employed appears to be well tolerated and active in the treatment of advanced breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis

A total of 35 women with advanced, metastatic breast cancer were treated with combination chemotherapy consisting of folinic acid 500 mg/m2 over 2 hours administered with 600 mg/m2 of 5FU at the midpoint of the folinic acid infusion weekly for 6 weeks, plus 60 mg/m2 of thiotepa on day 1 and day 28. The cycle was repeated every 8 weeks. Patients were evaluated for toxicity weekly. Response was evaluated at the end of each 8-week cycle. The median age was 55 years (range: 34-67). Prior to this study 30 patients had received chemotherapy; 13 had 1 regimen; 17 had 2 or more regimens; 8 had 5FU treatment. The overall response rate was 40% (1 complete and 13 partial); median duration of response was 4 months. Four of 8 patients with prior 5FU responded. Hematologic toxicity was significant; nadir WBC count: < 1,000/mm3 (10 patients); 1,000-1,999/mm (13 patients); nadir platelet count: < 20,000/mm3 (8 patients): 20,000-49,000/mm3 (8 patients); 50,000-99,000/mm3 (10 patients). We conclude that the combination of thiotepa, 5FU, and leucovorin had significant myelotoxicity and do not recommend its routine use in the treatment of metastatic breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Thiotepa

Sixty-four consecutive patients with locally advanced (n = 7) or metastatic breast cancer (n = 57), were treated with a combination of laevofolinic acid 100 mg m-2 plus 5-fluorouracil 340 mg m-2 i.v. on days 1-3, cyclophosphamide 600 mg m-2 i.v. on day 1 and epirubicin 90 mg m-2 i.v. on day 1. Epirubicin dose was progressively escalated by 10 mg m-2 per cycle up to 120 mg m-2 in the absence of dose-limiting toxicities. Granulocyte colony-stimulating factor (G-CSF) was given subcutaneously in order to prevent neutropenia. Epirubicin dosage could be increased to 100 mg m-2 in 53 patients (87%), to 110 mg m-2 in 31 patients (51%) and to 120 mg m-2 in 18 cases (30%). In most patients the dose-limiting toxicity was represented by myelosuppression. A statistically significant correlation was found between median white blood count (WBC) or absolute neutrophil count (ANC) nadir and epirubicin dose level (P = 0.009; P = 0.008). Moreover, a statistically significant correlation was observed between the number of chemotherapeutic cycles, nadir ANC and WBC and the occurrence of anaemia and thrombocytopenia of increasing severity. These data suggest the occurrence of progressive cumulative bone marrow toxicity. Although patients who reached different epirubicin levels showed differences in mean dose intensity, such differences were not statistically significant. No correlation was found between the increase in dose intensity and type, rate or duration of objective responses. In patients with metastatic breast cancer the overall response rate was 72% (95% CL 66-78%) with a 25% complete response rate. Median duration of response was 10 and 13 months respectively for complete and partial responses. All patients with locally advanced breast cancer had an objective response and underwent radical mastectomy. Projected median survival of the whole series of patients with metastatic breast cancer was 20 + months. These data demonstrate that the combination of 5-fluorouracil with laevofolinic acid, cyclophosphamide and epirubicin is very active against metastatic breast cancer. Use of G-CSF allows epirubicin dosage to be increased up to 120 mg m-2 cycle-1, but its use may be linked to the occurrence of sometimes severe cumulative haematological toxicity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Epirubicin; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Life Tables; Mastectomy, Radical; Menopause; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Remission Induction; Treatment Outcome

135 patients with locally advanced or metastatic colorectal cancer were entered into a phase III trial evaluating the efficacy of chemoimmunotherapy [recombinant interleukin 2 (rIL2)/5-fluorouracil (5-FU) and leucovorin (LV)] versus chemotherapy alone (5-FU/LV). A cycle of chemoimmunotherapy comprised a constant intravenous infusion of rIL2 at a dose of 18 x 10(6) U/m2/24 h for 120 h, followed by three bolus injections of 5-FU (600 mg/m2) and LV (25 mg/m2) at weekly intervals. Patients receiving chemotherapy alone received 5-FU/LV at the same dose at weekly intervals for 6 weeks followed by a rest period of 2 weeks, constituting one cycle of therapy. A maximum of 6 months therapy was given in both arms of the study. The response rates (complete and partial responses) were 17% in patients receiving rIL2/5-FU/LV versus 16% in those in the 5-FU/LV arm of the study. Median survival and progression-free survival were comparable for the two groups of patients, although there was a trend for a prolongation of survival in patients receiving chemoimmunotherapy compared with chemotherapy alone, beyond 12 months. Retrospective subgroup analyses revealed a significantly increased survival in poor prognosis patients (ECOG 1) treated with rIL2/5-FU/LV when compared to those receiving chemotherapy alone. Therefore, further studies evaluating the dose and duration of chemoimmunotherapy in patients with metastatic colorectal cancer seem warranted.

Topics: Adult; Aged; Colorectal Neoplasms; Female; Fluorouracil; Humans; Interleukin-2; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Survival Rate; Time Factors; Treatment Outcome

A phase II study was performed to assess the efficacy and toxicity of the combination of 5-fluorouracil (5-FU), leucovorin (LV), etoposide, and cisplatin (FLEP) in patients with advanced gastric carcinoma. A total of 46 consecutive, previously untreated patients with unresectable, measurable gastric carcinoma were treated with 300 mg/m2 LV, 100 mg/m2 etoposide, 500 mg/m2 5-FU, and 30 mg/m2 cisplatin on days 1-3 every 28 days. All courses were given on an outpatient basis. A total of 169 courses of treatment were given. In all, 18 of the 46 patients (39%) had an objective response [95% confidence interval (CI), 25%-54%] and 2 (4%) patients experienced a clinical complete response. The median duration of response was 5 months. The main side effects were hematological and gastrointestinal. Grade 3-4 toxicity was encountered as follows: leukopenia, in 9.5% of the courses; anemia, in 3%; thrombocytopenia, in 3%; nausea/vomiting, in 4%; and diarrhea, in 5%. Hospitalization due to fever and granulocytopenia was required in 5 patients, 3 of whom died of sepsis. In conclusion, FLEP shows moderate activity in patients with advanced gastric carcinoma, albeit at the cost of a high degree of toxicity. For this reason we do not recommend its use.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Epirubicin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Stomach Neoplasms; Survival Rate

Chemotherapy is most effective when applied during the biologically active stage of tumor cells. According to the authors' previous tumor marker kinetic study, methotrexate plus 5-fluorouracil (MF) was found to yield either a cytolytic effect in an MF-sensitive tumor cell population or a cytostatic effect in an MF-resistant population. In the latter, the suppressive effect was transient and the biologic activity resumed in one week after MF administration.. Based on this marker kinetic study, an alternating chemotherapy program was designed to study its antitumor and side effects. Methotrexate (M) (200 mg/m2) and 5-fluorouracil (F) (500 mg/m2) were administered intravenously on day 1 followed 24 hours later by leucovorin (L) (10 mg/m2 orally every 6 hours for 6 doses). Cyclophosphamide (C) 300 (mg/m2), doxorubicin (A) (50 mg/m2), and vincristine (V) (1 mg/m2) were given on day 8. The MFL/CAV was given every 4 weeks.. Forty-nine patients with metastatic breast cancer were enrolled; 41 were eligible. There were 5 complete and 23 partial remissions, producing a total response rate of 68%. In 15 patients with liver metastases, the response rate was 73% and the median survival 13.7 months, results superior to those previously reported for this subgroup of patients. Side effects were manageable.. This regimen, which can be given safely in an outpatient setting, yielded encouraging response and survival rates in patients with visceral-dominant disease with poor prognoses.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Methotrexate; Middle Aged; Neoplasm Metastasis; Pilot Projects; Remission Induction; Vincristine

Tegafur is an antimetabolite slowly metabolized to 5-fluorouracil in vivo. Protracted administration of oral tegafur is active in metastatic breast cancer, with reported response rates ranging from 29 to 44%. The addition of folinic acid could improve the efficacy of tegafur by means of biochemical modulation.. A prospective Phase II trial in patients with pretreated metastatic breast cancer was performed. The regimen consisted of oral tegafur (750 mg/m2/day) and oral folinic acid (45 mg/day) for 21 days, recycling at day 28.. Twenty-five patients were included. Eight partial responses were observed for an objective response rate of 32% (95% confidence intervals for response, 23-41%). The median duration of response was 7 months. According to WHO criteria, 24% of patients experienced grade 3 mucositis and 12% grade 3 diarrhea, but no other significant toxicities were observed. Twenty-eight percent of patients required dose reductions for toxicity.. A significant response rate with oral tegafur and folinic acid in patients with heavily pretreated breast cancer was found. This all-oral regimen, which could be safely administered on an outpatient basis, deserves further evaluation to define the role of folinic acid on the activity of tegafur in metastatic breast cancer.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Diarrhea; Humans; Leucovorin; Middle Aged; Mouth Mucosa; Neoplasm Metastasis; Prospective Studies; Remission Induction; Stomatitis; Tegafur

The combination of CDDP and ARA-C has shown some clinical efficiency as first-line therapy in advanced colorectal cancer. Our study was aimed to evaluate the therapeutic activity of this combination in advanced colorectal cancer who failed 5-fluorouracil (FU) and folinic acid (LV) regimen. Seventeen patients with measureable metastatic colorectal cancer who failed 5FU-LV therapy as first line (n = 14) or second line treatment (n = 3), entered the study. Three patients who recurred during adjuvant treatment with 5FU and levamisol, were also included. Median age was 59.5 (40-69). Performance status was as follows: 0 (n = 5), 1 (n = 11), 2 (n = 3), 3 (n = 1). Site of metastases included liver (n = 16), lung (n = 7), abdomen (n = 2), pelvic recurrences (n = 2), cutaneous (n = 1). Seven patients had 2 metastatic sites and two 3. The treatment was given as follows: ARA-C 75 mg/m2/day, days 1-3, followed 1 hour later by CDDP 30 mg/m2/day, days 1-3, every 28 days. The median number of cycles was 3 (range: 1-6 cycles). All patients but one were evaluable for both response and toxicity. Of these patients, 50% experienced severe hematologic toxicity and nonhematologic toxicity mainly consisted of fatigue and/or vomiting. No objective response was observed, but there were 3 stabilizations and 16 progressive diseases. Median time to progression was 10 weeks. Thus, the CDDP/ARA-C regimen is not of clinical value as salvage therapy in advanced colorectal cancer because of its toxicity and its lack of efficiency.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Cytarabine; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Treatment Outcome

Phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/II trial in outpatients: high-dose 5-FU (24-hour infusion)/FA (2-hour infusion preceding 5-FU) is given for 6 weeks (days 1, 8, 15, 22, 29, and 36), with paclitaxel (3-hour infusion) administered on days 1 and 22; 2 weeks' rest follows. Folinic acid 500 mg/m2 was administered throughout; the respective 5-FU doses for dose levels 1 through 3 were 1.5, 1.8, and 2.0 g/m2 with paclitaxel 135 mg/m2. Dose level 4 (500 mg/m2 FA, 2.0 g/m2 5-FU, and 175 mg/m2 paclitaxel) was chosen for phase II evaluation. To date, 46 patients with bidimensionally measurable disease (four each at dose levels 1, 2, and 3, and 34 at dose level 4) have been entered. The 12 patients treated at dose levels 1 through 3 were titrated to level 4 doses when phase II began; 35 patients are evaluable for response. The median age is 46 years, and the median number of metastatic sites is 2.5. Fourteen patients had received adjuvant chemotherapy, nine chemotherapy for metastasis, and 23 chemotherapy both adjuvantly and for metastasis. Of 31 anthracycline-treated patients, 27 had anthracycline-resistant disease. No dose-limiting toxicity appeared until dose level 4, when grade 3 or 4 leukopenia and diarrhea occurred in 15 and eight, respectively, of 108 cycles. Mild to moderate mucositis, hand-foot syndrome, myalgia, and nausea/vomiting occurred in 20% to 40% of cycles. One (3%) of the 35 patients had a complete response, 18 (51%) had partial responses, 14 (40%) had stable disease, and two (6%) had disease progression. Eleven (55%) of 20 evaluable patients with anthracycline-resistant disease responded (95% confidence interval, 34% to 76%). Median time to maximum response was 2 months, and the remission duration was 8+ months. Median survival time has not been reached. Paclitaxel and weekly high-dose 5-FU/FA was well tolerated and highly effective, even in patients with anthracycline-resistant metastatic breast cancer. The regimen can be administered safely to outpatients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Remission Induction; Salvage Therapy; Survival Analysis

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis

Bladder cancer is a chemosensitive tumour, however, there is no effective therapy for patients with metastatic disease who failed to respond or relapsed after prior treatment with cisplatin-based chemotherapy. Single agent 5-fluorouracil has modest activity in bladder cancer. The combination of 5-fluorouracil with folinic acid results in stabilization of the ternary complex of 5-fluorodeoxyuridine monophosphate-thymidylate synthetase-5,10 methylene tetrahydrofolate leading to increased DNA inhibition and increased cytotoxicity of 5-fluorouracil.. Fourteen evaluable patients with metastatic bladder cancer were treated with 5-fluorouracil at 300 mg/m2 and folinic acid at 200 mg/m2 daily for five days.. There were no complete or partial responses. One patient had a minor response and three patients had stable disease. Diarrhea and mucositis occurred in 25% of patients. There was one treatment-related death.. High dose folinic acid did not increase the cytotoxicity of 5-fluorouracil in metastatic bladder cancer after cisplatin failure.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Survival Rate; Urinary Bladder Neoplasms

A phase II study was performed to evaluate the clinical and immunological effects of a regimen of fluorouracil (5-FU) and folinic acid (FA) combined with thymopentin (TP-5) and interleukin-2 (IL-2) in the treatment of patients with metastatic colorectal cancer.. Forty-five evaluable patients with measurable colorectal cancer and no prior therapy for metastatic disease were treated with 5-FU 400 mg/m2/d and FA 200 mg/m2/d i.v. on days 1-5, TP-5 50 mg s.c. on days 8-11, and IL-2 9 MU/m2 s.c. twice daily on days 12-16. Cycles were repeated at 4-week intervals if toxicity had resolved. Immunological changes were evaluated in 13 patients and compared with a well matched series of 13 patients treated with the same regimen without TP-5.. Two complete responses and 17 partial responses were seen (42%; 95% confidence interval, 28% to 56%). Fifteen patients (33%) had stable disease. The median time to progression was 8.5 months and the median survival 13 months. Treatment was reasonably well tolerated, and there was no overlapping toxicity or interference between chemotherapy and biotherapy. Hematological and immunological changes during treatment were qualitatively similar to those expected with IL-2 +/- chemotherapy. Quantitatively, significant changes (higher levels of IL-2, CD25 and IFN-gamma, and lower levels of sIL-2R) were observed in patients given TP-5.. The combination of 5-FU + FA and TP-5 + IL-2 is effective in advanced colorectal cancer with acceptable toxicity. Immunological data suggest that TP-5 may modulate the action of IL-2 in the clinical setting. However, improved treatment approaches are needed, and the interactions between thymic hormones and cytokines should be further explored.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Interferon-gamma; Interleukin-2; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Receptors, Interleukin-2; T-Lymphocyte Subsets; Thymopentin

Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m2 by mouth every 6 h (700 mg/m2/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m2 was given intravenously immediately prior to 5-FU 375 mg/m2 intravenously on days 1-5. Mitoxantrone 6 mg/m2 was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m2 days 1-2, 5-FU 375 mg/m2 days 1-2, mitoxantrone 6 mg/m2 on day 2, and dipyridamole 175 mg/m2 every 6 h on days 0-3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Breast Neoplasms; Dipyridamole; Drug Interactions; Fluorouracil; Granulocytes; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis

In advanced colorectal cancer the addition of folinic acid (FA) has been shown to lead to increased activity, at least in terms of response rate, in comparison with 5-fluorouracil (5FU) alone. Similarly, interferon-alpha (IFN) is able to potentiate 5FU, although high doses cause heavy toxicity. Given the different mechanisms of action of the two agents, the double modulation of 5FU deserves clinical evaluation. In a multicenter study (involving both primary care and referral institutions) 63 patients with advanced colorectal cancer, previously untreated with chemotherapy, received, in an outpatient setting, FA (200 mg/m2 i.v. bolus) + 5FU (400 mg/m2 i.v. in 15 min) for 5 consecutive days every 4 weeks + IFN 3 x 10(6) U on alternate days, starting 1 week before chemotherapy. During the 5 days of 5FU + FA, IFN was administered daily. The antitumour activity, the impact on response duration and survival and toxicity of the combination were evaluated according to WHO criteria. Of the 63 enrolled patients, 56 were evaluable: there were 2 complete responses (3%) and 13 partial responses (21%), giving an objective response rate of 24% (95% confidence interval 13-35%); no change was observed in 17 cases and progressive disease in 24. Median duration of response was 9 months and median survival (all patients) 13 months. Toxicity was acceptable, even though 4 patients presented reversible grade 4 side-effects (2 mucositis and 2 diarrhoea). With this schedule and these doses, addition of IFN did not lead to any increase in the activity of 5FU + FA. In colorectal cancer, further clinical studies with these drugs should be based on a deeper experimental knowledge of their mechanisms of interaction.

Topics: Adult; Aged; Colonic Neoplasms; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Rectal Neoplasms

Bolus/infusional 5-fluorouracil (5-FU) and folinic acid (FA) is reported to be highly active [partial response (PR) = 54%, median survival 18 months] in patients with metastatic colorectal carcinoma (MCCa). To confirm this level of activity, we conducted a retrospective analysis of 95 previously untreated patients with MCCa treated with FA by 2 h i.v. infusion (200 mg m-2) followed by 5-FU bolus/22 h i.v. infusion (300-500 mg m-2) on days 1 and 2 every 2 weeks. Thirty patients also received N-(phosphonacetyl)-L-aspartate (PALA), 250 mg m-2, 24 h prior to 5-FU/FA. In 81 evaluable patients, the response rate was low: PR = 11%, stable disease (SD) = 36% and median survival = 8 months. There was an improvement in survival with increased 5-FU dosage (500 mg m-2) [relative hazard (RH) = 0.38, 95% CI 0.21-0.70], controlled for age, primary site, PALA, liver function and performance status. Good performance status (PS 0 or 1) was also associated with improved survival (RH = 0.21, 95% CI 0.10-0.46). Response, survival and toxicity were not altered by the co-administration of PALA. Bolus/infusional 5-FU (500 mg m-2) and FA was well tolerated. WHO toxicities (grade 3) were: mucositis, 2%; diarrhoea, 14%; nausea and vomiting, 5%. In light of the apparent dose effect, poor response and low toxicity, we recommend that regimes incorporating higher 5-FU dosages are explored and prospectively validated before bolus/infusional 5-FU becomes accepted standard practice.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Survival Analysis

A phase II study to test the toxicity and the efficacy of a weekly combination of Mitoxantrone, 5-Fluorouracil and L-Leucovorin (MFL) was carried out in 43 patients with metastatic breast cancer. Chemotherapy consisted of mitoxantrone 4 mg/m2, 5-fluorouracil 375 mg/m2, and L-leucovorin 100 mg/m2 on day 1, weekly. Patient characteristics were: median age 53 years (range 36-65); estrogen receptor (ER) status was known in 26 patients and of these 15 (57.7%) patients were ER-positive and 11 (42.3%) ER-negative. Of the 43 patients, 25 (58.1%) and 18 (41.9%) patients had received prior adjuvant chemotherapy and prior adjuvant endocrine treatment, respectively. MFL was administered to 22 (51.1%) patients as first line chemotherapy for advanced disease, while 21 (48.9%) patients had received 1 to 2 cytotoxic regimens for metastatic disease. The dominant sites of metastases were: soft tissue in 11 (25.5%) patients, bone in 8 (18.6%) patients and viscera in 24 (55.9%). All patients were assessable for toxicity: only 8 patients experienced WHO grade 3 leukopenia. Thrombocytopenia, diarrhea, stomatitis, and nausea/vomiting were negligible. Anemia and alopecia were not observed. Thirty-nine patients were assessable for response: overall response rate was 28.2% (complete response 7.7% and partial response 20.5%). Median duration of response was 12 months (range 6-34). Patients with no prior anthracyclines had a 42.1% response rate compared to 15% in patients who had received anthracyclines. Median overall survival of the 43 patients was 6 months (range 1-34). Weekly MFL is a well-tolerated and a moderately effective regimen for the treatment of metastatic breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Treatment Outcome

To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT; Taiho Pharmaceutical Ltd, Tokyo, Japan) plus oral calcium leucovorin in the treatment of patients with advanced colorectal carcinoma.. Forty-five patients with advanced, bidimensionally measurable metastatic colorectal carcinoma were enrolled onto the trial. None of the patients had received prior chemotherapy or biologic therapy for advanced disease. Patients received either 350 or 300 mg/m2/d UFT plus 150 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two courses of therapy.. Eighteen patients (three treated at 350 mg/m2/d and 15 at 300 mg/m2/d) had partial responses, and one patient had a complete response (response rate, 42.2%; 95% confidence interval, 28% to 58%). Responses were observed in sites that included liver (n = 18), lung (n = 6), and bone (n = 1). Of seven patients who received 350 mg/m2 UFT, prolonged grade 3 diarrhea developed in five; this resulted in a reduction in the UFT starting dose to 300 mg/m2/d in the remaining 38 patients. Grade 1 or 2 toxic effects included diarrhea, nausea, vomiting, abdominal cramping, anorexia, fatigue, oral mucositis, excessive lacrimation, and rash. Among 38 patients who received the 300-mg/m2/d dose, grade 3 toxic reactions included diarrhea (n = 4), vomiting (n = 2), abdominal cramping (n = 1), and fatigue (n = 2).. UFT 300 mg/m2/d plus oral leucovorin 150 mg/d administered for 28 days demonstrated significant activity against metastatic colorectal carcinoma. This oral regimen was well tolerated and devoid of the neutropenia or significant oral mucositis that complicates intravenous schedules of fluorouracil (5-FU) plus leucovorin. The results of this clinical trial will serve as the basis for a randomized phase III study to compare this oral schedule of UFT plus leucovorin with intravenous 5-FU plus leucovorin to determine the relative efficacy, impact on quality of life, and cost of the two regimens.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Leucovorin; Male; Middle Aged; Nausea; Neoplasm Metastasis; Tegafur; Uracil

The response of hormone-refractory metastatic prostate cancer to chemotherapy is poor. The antitumour activity of single agent 5-fluorouracil (5-FU) is approximately 15%. Folinic acid is a reduced folate which when combined with 5-FU augments the activity of 5-FU by stabilizing the ternary complex of 5-deoxyuridine monophosphate-thymidylate synthetase-5,10 methylene tetrahydrofolate, resulting in increased DNA inhibition and in increased cytotoxicity of 5-FU.. We used the combination of 5-FU at 300-370 mg/m2 and folinic acid at 200 mg/m2 daily for five days in 16 patients with hormone-refractory metastatic prostate cancer.. A total of 15 evaluable patients were treated. There were no complete or partial responses. Seven patients had stable disease. Diarrhea constituted the most common non-hematologic toxicities (67%). Four patients experienced grade 3 and 4 neutrophil toxicity. There was one treatment-related death from an acute enterocolitis and peritonitis in a patient with grade 4 neutropenia.. High dose folinic acid did not increase the cytotoxicity of 5-FU in hormone-refractory metastatic prostate cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Prostatic Neoplasms

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Salvage Therapy

Between February 1991 and July 1992, 79 previously untreated patients with metastatic colorectal carcinoma were enrolled in a phase II study of combined 5-fluorouracil (5-FU) and l-folinic acid (FA). 5-FU 370 mg/m2/day was administered for 5 consecutive days as an intravenous (i.v.) bolus injection preceded by l-FA 100 mg/m2/day with the same administration modality. Treatment was given every 4 weeks until progression. 79 patients were evaluable for toxicity and 64 for response. 2 patients (3%) achieved a complete remission and 8 (12.5%) a partial remission, 33 (52%) had stable disease and 21 patients (33%) had progressive disease. Median duration of remission was 32.5 weeks and median survival for all evaluable patients was 64.5 weeks. Substantial to severe side-effects occurred in 39% of patients. Dose-limiting toxicity (grade 3-4) was mainly diarrhoea (18%) and mucositis (15%). Nausea/vomiting, cutaneous toxicity, leucopenia, alopecia and conjunctivitis of grade 3-4 occurred respectively in 6, 4, 2.5, 1 and 1% of cases. Toxicity appeared to be substantially similar to that characteristic of combined 5-FU and the chiral mixture of d,l-FA. Efficacy was within the range of that observed with the 5-FU/d,l-FA combination, although at the lower level.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mouth Mucosa; Neoplasm Metastasis; Remission Induction; Stomatitis; Treatment Outcome; Vomiting

In a Phase I-II clinical trial, 19 ambulatory women with metastatic breast cancer were treated with a combination of mitoxantrone, 5-fluorouracil, and leucovorin (MFL). The planned schedule of mitoxantrone intravenously (i.v.) on day 1 with 5FU and leucovorin (days 1, 8, and 15) was better tolerated on a day 1 and day 8 schedule. Dose-limiting toxicity was found to be granulocytopenia with very little subjective toxicity encountered. Platelet toxicity and more profound granulocyte toxicity appeared to occur in patients with liver metastases. Since most patients did not have easily measurable disease, a response rate could not be determined, although at least four patients had probable antitumor responses. We conclude that doses of M (7.5 mg/m2 i.v. day 1) and 375 mg/m2 days 1 and 8 of F and L should be the starting doses for Phase II trials on this treatment schedule and should be well tolerated subjectively. Dose escalation and deescalation schemata should be included in a Phase II study design, recognizing that some patients may not encounter toxicity at these doses, while patients with liver metastases may develop inordinate toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Treatment Outcome

Authors carried out a review of 40 cases of recurrent and/or metastatic nasopharyngeal carcinoma (NPC) treated with cisplatin-based chemotherapy at the Division of Othorhinolaryngology and the Service of Chemotherapy of the University of Palermo between July 1984 and July 1992. All patients were treated with regimens comprising high dose cisplatin (80-100 mg m-2). Histologically there were 29 squamous cell and 11 undifferentiated NPC. Thirty-nine patients were evaluable for response and toxicity. The overall response rate was 64%, with a 20.5% complete response rate and a 43.5% partial response rate. The mean duration of complete responses was 10.2+months, while that of partial responses was 8.6+months. The mean survival of the whole group was 11.4+months, with four patients alive after 2 years of follow-up. No statistically significant difference in response rate and survival was found between patients with metastatic disease and those with locoregional recurrency, and between patients with squamous cell NPC and those with undifferentiated histology. The employed regimens have been generally well tolerated. These data confirm that NPC is a neoplasm highly responsive to chemotherapy. However, duration of objective response and survival are still largely unsatisfactory.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies

In patients with diffuse large cell lymphoma treated with chemotherapy the presence of high levels of serum beta 2 microglobulin has been considered as a bad prognostic factor. Until now, attempts to detect early relapse in patients with diffuse large cell lymphoma have been sparse. To address this issue we began a prospective clinical trial to evaluate the role of different clinical, laboratory and radiographic tests in the detection of early relapse in non-Hodgkin's lymphoma (NHL). Only serum beta 2 microglobulin levels had clinical significance and 26 of 53 patients (49%) had abnormal levels, 3 to 23.1 months (mean 8.5 months) before evident relapse. Elevated serum lactic dehydrogenase (LDH) levels and beta 2 microglobulin were observed in six patients and all relapsed, suggesting that the combination of these two tests should be considered in future prospective clinical trials in order to define the utility of both tests to detect early relapse. This information may allow us to begin chemotherapy when the tumor mass is still low thereby making the probability of achieving a long second remission more likely.

Topics: Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Biomarkers, Tumor; Bleomycin; Cyclophosphamide; Dexamethasone; Doxorubicin; Follow-Up Studies; Humans; L-Lactate Dehydrogenase; Leucovorin; Life Tables; Lymphoma, Large B-Cell, Diffuse; Methotrexate; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Predictive Value of Tests; Prospective Studies; Remission Induction; Survival Analysis; Vincristine

Metastatic breast cancer remains an incurable disease; therefore, both the efficacy and the toxicity of palliative chemotherapy are important considerations. Mitoxantrone and 5-fluorouracil (5-FU) with high dose leucovorin are active drugs in the treatment of breast cancer, and both can be given with relatively few side effects. We evaluated the efficacy and toxicity of these agents in a combination regimen for the treatment of metastatic breast cancer.. In a phase II study, we treated 35 women with metastatic breast cancer with the following regimen: mitoxantrone 12 mg/m2 i.v. day 1; leucovorin 300 mg i.v. over 1 hour followed by 5-FU 350 mg/m2 i.v. push on days 1, 2 and 3; courses repeated every 21 days. Responding patients received a total of 6-8 courses. Most patients were receiving second-line chemotherapy for metastatic breast cancer, but some were receiving first-line therapy following failure of adjuvant chemotherapy.. Twenty of 31 assessable patients (65%) had objective responses; in addition, 2 of 4 patients with bone-only metastases had sustained symptomatic responses. Toxicity was mild and the regimen was well tolerated. The activity of this drug combination has been verified in several other phase II studies.. The combination of mitoxantrone, 5-FU and high-dose leucovorin provides an attractive option for second-line chemotherapy of metastatic breast cancer. The efficacy of this combination in first-line therapy is currently being compared to cyclophosphamide, methotrexate and 5-FU (CMF) in a randomized trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Palliative Care

Patients presenting with advanced or metastatic colorectal carcinoma were randomized to treatment with either 5-Fluoro-Uracil + leucovorin or 5-Fluoro-Uracil + interferon alpha-2-a. Longitudinal series of Carcino-embryonic-antigen were obtained and analyzed with a dynamic model in seven of 16 patients had CEA levels above 10 ng ml-1. Clinical evaluation based on X-ray, ultrasound and CT-scans showed a partial response to the given treatment in three of the seven patients. The dynamic model consistently estimated the maximal accumulated cell kill (approximately three logs) in the patients experiencing a clinical response. The remaining four patients with CEA levels above 10 ng ml-1 showed some reduction in CEA as a consequence of the treatment cycles, although no clinical response could be established. No response was seen among the remaining nine patients with CEA levels below 10 ng ml-1.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Colorectal Neoplasms; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies; Recombinant Proteins

Chemotherapy of colon cancer has used the modulation of 5-fluorouracil (5-FU) by leucovorin; however, early studies indicate that leucovorin with fluorodeoxyuridine (FUDR) may be clinically superior. The authors report their experience in patients with metastatic colorectal cancer.. One hundred twelve evaluable patients with metastatic colorectal cancer were treated with leucovorin and FUDR. Leucovorin was given by continuous intravenous infusion at 500 mg/m2/day on days 1-6, and FUDR was given by intravenous push on days 2-6 at 3:00 p.m. daily, with doses ranging from 270-1350 mg/m2/day.. This regimen was well tolerated with dose-limiting toxicity of diarrhea and stomatitis, while hematologic toxicity was minimal. At least one chemotherapy regimen had previously failed in 90 of 112 patients (80%). Twenty major responses greater than or equal to partial remission, lasting from 2-40+ months, were observed in this patient population for an overall response rate of 18%. Twelve of 22 previously untreated patients (55%) had major responses. Overall survival of previously untreated patients was 73% (14 of 19) and 50% (11 of 22) at 1 and 2 years, respectively. Of 66 patients who had received prior leucovorin-5-FU (LVFU) therapy with subsequent disease progression, 4 had major responses lasting 95, 241, 350, and 432 days, respectively.. These data suggest that the modulation of FUDR by leucovorin may have clinical use. The recommended starting dose of FUDR is 800 mg/m2/day on days 2-6, with subsequent escalation each month in those patients who do not display stomatitis.

Topics: Adult; Aged; Colorectal Neoplasms; Diarrhea; Drug Therapy, Combination; Female; Floxuridine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Remission Induction; Stomatitis; Survival Rate

60 patients with metastatic breast cancer were entered in a phase II study using folinic acid, 5-fluorouracil bolus and infusion and mitoxantrone with or without cyclophosphamide. 47 had measurable visceral metastases and 13 had exclusively bone metastases. 36 had received previous adjuvant or metastatic treatment (33/36 with anthracycline-based regimens). Overall response rate in visceral metastatic patients was 57.1% [95% confidence interval (CI) 35.4-78.8%]; 45.5% and 70% in previously and non-previously treated patients, respectively; duration of response was 9 and 13 months, respectively. 10 out 13 patients with exclusive bone metastases improved for a median time of 18 months. Median survival was 22 months for the 60 patients; 18 and 31 months for previously and non-previously treated patients, respectively. Cyclophosphamide was scheduled only in the absence of nadir grade 4 neutropenia. However, this toxicity occurred in the first 7 patients. For this reason, we chose to avoid cyclophosphamide in patients over 60 years, or with a performance status of 1-2, or who had received previous chemotherapy. Overall, cyclophosphamide was stopped due to nadir grade 4 neutropenia in 17/24 patients for whom this drug was planned. When mitoxantrone, 5-fluorouracil and folinic acid were used at the doses scheduled, the addition of cyclophosphamide appeared feasible in only about 25% of the patients. Furthermore, survival was identical for patients receiving or not receiving cyclophosphamide. Therefore, cyclophosphamide does not contribute substantially to this regimen. This study confirms the value of folinic acid, 5-fluorouracil and mitoxantrone in metastatic breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Neutropenia; Prognosis

Prolonged infusional 5-fluorouracil (5-FU) and bolus 5-FU modulated by leucovorin are associated with higher response rates than bolus 5-FU alone. Cisplatin enhances 5-FU cytotoxicity in some preclinical models.. The authors tested the feasibility of combining concurrent infusional leucovorin (500 mg/m2/d) with protracted infusional 5-FU (200 mg/m2/d) and weekly bolus cisplatin (20 mg/m2) in 22 patients with metastatic colorectal cancer.. Four partial responses (PR) were noticed among 21 evaluable patients (19%). The median time to treatment failure and median survival were 6 months and 11 months, respectively. All but two patients required 5-FU dose reduction after a median of 2 weeks because of mucositis. However, severe mucositis and diarrhea occurred in only 18% and 5% of the patients, respectively. Palmar-plantar erythrodysesthesia of mild to moderate severity occurred in 55% of patients. Megaloblastic changes were evident in the peripheral blood during therapy, and may reflect prolonged DNA-directed toxicity of 5-FU. The median tolerated dose level of 5-FU was 113 mg/m2/d (range, 64-150 mg/m2/d). Mean steady-state plasma concentrations (Cpss) of 5-FU appeared to increase linearly from 0.19 microM to 0.39 microM over the dose range 64 to 200 mg/m2/d. Patients with grade 2 gastrointestinal toxicity had significantly higher 5-FU Cpss than patients with grade 0 or 1 toxicity.. The early onset of toxicity with this regimen of protracted infusional 5-FU/high-dose leucovorin and weekly cisplatin required marked attenuation of the 5-FU dose intensity, and the results were no better than that expected with infusional 5-FU alone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Rectal Neoplasms; Survival Analysis; Treatment Failure

To test the activity of a regimen of interferon alfa-2a (IFN alpha-2a) 5 x 10(6) U/m2 subcutaneously (SC) days 1 through 7 combined with leucovorin 500 mg/m2/d intravenously (IV) over 30 minutes and fluorouracil (5-FU) 370 mg/m2/d through IV push 1 hour after leucovorin days 2 through 6 in a phase II study.. Forty-six patients with a good performance status (PS) with measurable colorectal cancer and no prior therapy for metastatic disease were entered. Cycles were repeated at 3-week intervals if toxicity had resolved. The 5-FU dose was increased by 15% if toxicity was mild, and decreased by 15% for grade 3 to 4 nonhematologic or grade 4 hematologic toxicity.. Three complete responses (CRs) and 21 partial responses (PRs) were seen among 44 assessable patients (54%; 95% confidence interval, 39% to 70%). A moderately strong association was noted between PS and response: PS O (n = 26), two CRs and 15 PRs (65%); PS 1 (n = 13), one CR and six PRs (54%); PS 2 (n = 5), zero CRs and zero PRs (0%; two-tailed P = .026). With a median follow-up duration of 18.8 months, the median time to treatment failure (TTF) and survival were 7.8 months and 16.3 months, respectively. Doses were escalated to 425 mg/m2/d 5-FU in 10 patients, but only four tolerated the higher dose. When expressed as the most severe degree of toxicity experienced by each patient across all cycles, grade 3 to 4 toxicity of the following types was observed; mucositis, 37%; diarrhea, 40%; rash, 7%; fatigue, 14%; granulocytopenia, 13%. Dose-limiting toxicity at 370 mg/m2/d 5-FU eventually occurred in 28 patients (61%). Twelve patients (26%) required an IFN alpha-2a dose reduction for constitutional toxicity.. This regimen has promising activity in advanced colorectal cancer, particularly in patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Survival Analysis

In three consecutive phase II trials, 5-fluorouracil (5FU)-low dose leucovorin (20 mg/m2/day) was delivered in two 5-day courses during the first (d1 to d5) and the last (d29 to d33) week of a limited pelvic irradiation (45 Gy, 5 weeks, 25 fractions) in patients with locally extended rectal cancer. The three trials differed only by the 5FU dose in the chemotherapy (CT) schemes. In trial 1 (first CT course 5FU dose 425 mg/m2/day, second CT course 370 mg/m2/day), 16 patients were included. 5 patients suffered a grade 3+ toxicity and the compliance was 63%. In trial 2 (first and second CT course 5FU dose 370 mg/m2/day), 53 patients were included. 5 patients suffered a grade 3+ toxicity. The compliance was 94%. In the trial 3 (first and second CT course 5FU dose 350 mg/m2/day), 16 patients were included. 1 patient suffered a grade 3 toxicity and the compliance was 100%. The overall response rate (complete and partial responses) of local disease and distant metastasis were 87 and 7%, respectively. 43 patients were operated on after a mean delay of 8 weeks. Among the 41 macroscopic complete resections, 6 (14.6%) were sterilised and 12 (29.3%) were classified Asler-Coller A/B1. Regression curve analysis using either grade 3+ toxicity or incomplete treatment as an end point against the 5FU dose indicates that a 350 mg/m2/day 5FU dose is advisable for a phase III adjuvant multicentre trial.

Topics: Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Patient Compliance; Rectal Neoplasms; Treatment Outcome

34 patients with metastatic or recurrent transitional cell carcinoma (TCC) of the urothelium were treated with cisplatin 100 mg/m2 plus methotrexate 250 mg/m2 with folinic acid rescue every 3 weeks. A response rate of 55% was achieved with two complete and 15 partial responses in 31 evaluable patients. The overall median survival was 7 months, 9 months for responding and 4 months for non-responding patients. Toxicity was generally moderate. However, 1 patient with previous infectious problems died of neutropenic sepsis. Overall, 83% of the scheduled doses of cisplatin and 96% of the scheduled doses of methotrexate were given. In conclusion, this schedule of the combination of cisplatin and methotrexate did not improve response rate or survival compared with previous studies of this two-drug combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms

Preclinical studies suggest that the biochemical effects of N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate carbamoyltransferase (ACTase), may increase the metabolic activation of 5-fluorouracil (5-FU) and enhance its cytotoxicity through both RNA- and DNA-directed mechanisms. In this Phase I trial, 22 evaluable patients with adenocarcinoma of the gastrointestinal tract were entered at escalating doses of 5-FU starting at 1150 mg/m2/day given as a concurrent 72-h i.v. infusion with a fixed dose of leucovorin (LCV), 500 mg/m2/day. The dose of 5-FU was escalated within patients according to individual tolerance, and then PALA at 250 mg/m2 was added 24 h prior to the initiation of the 5-FU/LCV infusion of the subsequent cycle. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 3 of 5 patients treated with 2300 mg/m2/day 5-FU; therefore, the recommended dose of 5-FU with concurrent LCV is 2000 mg/m2/day. Twenty-seven additional patients were then treated with escalating doses of PALA ranging from 375 to 2848 mg/m2, i.v., followed 24 h later by 2000 mg/m2/day 5-FU with high-dose LCV. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 2 of 3 patients entered at 2848 mg/m2 PALA. Dose-limiting mucositis and skin rash ultimately required both PALA and 5-FU dose reductions in 4 of 6 patients treated with 1899 mg/m2 PALA. Toxicity was similar, however, in patients receiving PALA at doses ranging from 375 to 1266 mg/m2. The mean steady-state plasma concentration of 5-FU at 2000 mg/m2/day was 6.5 +/- 0.9 microM; patients with 5-FU levels > 9 microM had a significantly higher incidence of serious gastrointestinal and hematological toxicity. Compared to each patient's own baseline, a significant trend for decreasing ACTase activity with increasing PALA dose was evident using cytosol isolated from peripheral blood mononuclear cells 24 h after PALA treatment (P2 = 0.01). PALA < or = 844 mg/m2 failed to appreciably inhibit ACTase activity at 24 h in most patients; furthermore, a decrease in ACTase activity by > 50% from baseline was seen in only 29% of cycles. More consistent inhibition of ACTase activity was seen with PALA > or = 1266 mg/m2. Even with the highest PALA doses, however, ACTase activity returned to baseline by 96 h in most patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartate Carbamoyltransferase; Aspartic Acid; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Monocytes; Neoplasm Metastasis; Phosphonoacetic Acid

We report the results of a phase III trial in which we compared 5-fluorouracil (5-FU) to 5-FU and folinic acid (FA) in 150 previously untreated metastatic colon cancer patients. Patients were randomized in the ratio of 1:2 to receive 5-FU (370 mg/m2, i.v., for 5 days) in arm A or equidose 5-FU plus FA (200 mg/m2, i.v., for 5 days) for arm B, each cycle being repeated every 4 weeks. Five of 49 evaluable arm A patients (10.2%) and 31 of 97 arm B (31.9%) achieved a complete or partial response (p < or = 0.01). Median survival time of arm A patients was 6 months (mean: 6.18), while it was 8 months (mean: 9.01) for arm B cases (p < or = 0.05). In conclusion, our data indicate that FA can enhance 5-FU activity and that this combination is an effective palliative treatment for metastatic colon cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Rate

A total of 25 patients with metastatic renal cancer were treated on a phase II protocol with 5 days of continuous-infusion fluorodeoxyuridine (FUDR), (0.1 mg/kg daily) together with high-dose oral leucovorin (100 mg 4 h) and daily x6 high-dose interferon-alpha 2b (30 x 10(6) IU/m2). Despite the good performance status of the patients and the inclusion of 14 previously untreated patients in the cohort, no response was observed among the 20 evaluable patients. Toxicities included high fever, moderate anemia, transient leukopenia, transient and mild elevations of transaminases, and moderate to severe nausea, vomiting, diarrhea, and mucositis. There were also two episodes each of confusion, fluid retention, and pancreatitis and one episode of increased creatinine levels. During the study three deaths occurred, two of which were possibly therapy-related. Despite previous reports of activity of FUDR in metastatic renal cancer, the present regimen cannot be recommended.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Combined Modality Therapy; Floxuridine; Humans; Infusions, Intravenous; Injections, Subcutaneous; Interferon-alpha; Kidney Neoplasms; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Time Factors

A high rate of response to 5-fluorouracil (5FU) and alpha-interferon (alpha IFN) combination therapy has been reported in metastatic colorectal cancer patients. Therefore, designed a trial of high-dose continuous-infusion 5FU, oral leucovorin (LV), and alpha IFN in this group of patients. Because this combination has not previously been tested and severe toxicity has been reported for 5FU and alpha IFN combination therapy, we conducted a phase I trial in which 11 patients presenting with previously untreated metastatic colorectal cancer were treated with escalating doses of alpha IFN together with fixed doses of 5FU and LV. WHO grade III toxicity consisting mainly of oral mucositis was noted in four patients. No grade IV toxicity occurred. Although alpha IFN may enhance the toxicity of 5FU, the toxicity of this regimen remained manageable. Three partial responses were noted.

Topics: Adenocarcinoma; Adult; Aged; Colorectal Neoplasms; Drug Evaluation; Drug Therapy, Combination; Fluorouracil; Humans; Infusions, Intravenous; Interferon-alpha; Leucovorin; Middle Aged; Neoplasm Metastasis; Remission Induction; Time Factors

Several reports on fluorouracil (5-FU) and alfa interferon (IFN-alpha) combination therapy in patients with advanced colorectal cancer have been published. In our study high-dose continuous infusion 5-FU (60 mg/kg per 48 hours), oral folinic acid (FA) (8 x 90 mg during 5-FU), and IFN-alpha three times weekly were combined. Because the addition of IFN-alpha has not been tested before, and serious toxicity of 5-FU plus IFN-alpha therapy has been reported, the IFN-alpha dose was escalated from 3 to 10 million units (MU)/dose in the first 11 patients. Grade 3 toxicity was noted in four patients, and consisted mainly of oral mucositis. No grade 4 toxicity occurred. Three partial responses were noted. Preliminary results of a phase II study, in which all patients received IFN-alpha at 10 MU/dose, show grade 3 and 4 toxicities in 24% and 4% of patients, respectively. This compares favorably with other trials in which 5-FU and IFN-alpha was used without FA.

Topics: Administration, Oral; Adult; Aged; Colorectal Neoplasms; Drug Administration Schedule; Drug Evaluation; Fluorouracil; Humans; Infusions, Intravenous; Interferon-alpha; Leucovorin; Middle Aged; Neoplasm Metastasis

In a clinical phase II study, 23 patients with progressive metastatic colorectal cancer and failure after first-line chemotherapy with fluorouracil (5-FU) and folinic acid (FA) were treated with a 5-day continuous infusion of recombinant interleukin-2 (IL-2), 3 x 10(6) cetus U/m2/d, followed after a rest period of 2 days by 5-FU, 600 mg/m2/d, and FA, 300 mg/m2/d over an additional 3 days. After two to four treatment cycles, eight of 22 evaluable patients (36%) revealed antitumor responses, with three partial remissions and five minor responses or stable disease. Side effects consisted most frequently of fever, nausea and vomiting, an elevation of liver enzymes, hypotension, and skin toxicity, and required a 50% reduction of IL-2 dose in 17 of 71 treatment courses (24%). In four of the 23 patients (18%), treatment had to be stopped completely. These data indicate a significant antitumor activity of IL-2 combined with 5-FU/FA therapy in chemotherapy-resistant colorectal cancer. Hence, in spite of a substantial treatment-related toxicity, further studies are warranted to substantiate these findings and to elucidate the underlying mechanisms of the IL-2-5-FU/FA combination therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Evaluation; Fluorouracil; Humans; Interleukin-2; Leucovorin; Middle Aged; Neoplasm Metastasis

Modulation of fluorouracil (5-FU) therapy with folinic acid (FA) in advanced colorectal adenocarcinoma produces a doubled increase in remission rates, but one important study with another modulation of 5-FU with interferon alfa 2a (IFN-alpha-2a) had better results. In the fact that both modulations have different mechanisms of interaction, it seems hopeful that both have additive or synergistic effects and they give further increases of remission rates. Twenty-three patients with proven progressive advanced colorectal cancer were treated with 5-FU, FA, and IFN-alpha-2a in three different regimens. IFN-alpha-2a was given subcutaneously in a dose of 5 MioU per day during 5-FU treatment. In the first regimen FA (500 mg/m2) was administered in a short time infusion (30 minutes) while 5-FU (1,000 mg/m2) was given in a 24-hour continuous infusion with weekly intervals. In regimen 2 and 3 FA/5-FU treatment was given on days 1 to 5 every 3 to 4 weeks. The difference was time and dose of the 5-FU infusion (600 mg/m2 in 4-hour versus 350 mg/m2 by push injection). Three patients with isolated liver metastases and one patient with local recurrence of rectal carcinoma received regional therapy with higher 5-FU doses. Dose escalation was carried out in all regimens when possible (toxicity less than or equal to World Health Organization [WHO] grade 1). Objective response rates were reached in nine of 23 patients with two complete remissions (one in regional and systemic treatment) with a mean duration of 6 months. Eight patients had stable disease and six had therapy failure. In pretreated patients no complete remission was reached; three of seven had partial remission, two no change, and two progressive disease. Severe toxicity occurred in 12 of 23 patients with mucositis WHO grade 4 in one patient, grade 3 in two, hematotoxicity grade 3 in three, and cutaneous toxicity in two. Eight of twenty-three patients had alopecia grades 2 and 3. These early results of our phase II study with limited patients shows no significant advantage of double modulation in comparison to the well established results of FA/5-FU therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Rectal Neoplasms

In a prospective randomized multicentre trial 139 patients with metastatic colorectal carcinoma (70 men, 69 women; age 35-81 years) were given palliative treatment with fluorouracil (400 mg/m2 daily for 5 days) alone or combined with folic acid (100 mg/m2 before each dose of fluorouracil). Both groups were comparable in respect of age, sex, Karnofsky index and number of localisations of metastases. The criterion for starting the treatment was progression of the malignancy or clinical symptoms caused by the tumour. Resulting remission rates (fluorouracil monotherapy vs combination with folic acid) were: complete or partial remission, 9 vs 16%; arrest of tumour growth, 20 vs 60%; progression 71 vs 24%. Peripheral side effects, such as stomatitis and diarrhoea, were similarly frequent with the two treatment regimens and reasonably tolerable. Median survival time for the fluorouracil monotherapy was 7.24 months from onset of treatment, and 9.1 months from the time that any metastases were diagnosed. The combination treatment with folic acid achieved a significantly longer median survival time (P less than 0.0001), 14.98 months from treatment onset and 16.3 months from metastasis diagnosis. The higher rate of response and the significantly prolonged survival time signify an improvement of the therapeutic profile of fluorouracil by addition of folic acid in the palliative therapy of colorectal carcinomas.

Topics: Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Prospective Studies; Time Factors

The mechanisms of biochemical modulation of 5-fluorouracil (5-FU) cytotoxicity by folinic acid (FA) have been elucidated, and the clinical use of this combination has improved response rates and survival in patients with metastatic colorectal cancer. Recently, Phase II trials also showed potential synergism between alpha-2a-interferon (rHuIFN-alpha 2a) and 5-FU. Therefore, a Phase I trial of these three agents 5-FU, FA, and rHuIFN-alpha 2a was conducted in patients with metastatic colorectal cancer. The drugs were given over 5 days, with dose escalation of either rHuIFN-alpha 2a or 5-FU. Fifty-five eligible patients were treated at eight dosing levels. The maximal tolerated dose (MTD) was as follows: 5-FU 430 mg/m2/d intravenously (IV) on days 1 to 5, FA 200 mg/m2 IV on days 1 to 5, and rHuIFN-alpha 2a 4.0 x 10(6) U/m2/d subcutaneously on days 1 to 5. The dose-limiting toxicities were mucositis and neutropenia. Objective responses were seen at most dosing levels, and overall 15 of 55 patients (27%; 95% confidence interval, 16% to 41%) responded (median duration, 6.5 months). A Phase II trial using the MTD is ongoing.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Survival Analysis

A significant increase in the dose intensity of chemotherapy with fluoropyrimidines and platinum complexes has resulted from selective circadian timing and/or circadian modulation of the infusion rate. The relevance of such chronopharmacologic strategy for improving the outcome of metastatic colorectal cancer was evaluated in an extended Phase II clinical trial involving 93 patients. Of these, 49% previously had received chemotherapy and/or radiation therapy. The drugs 5-fluorouracil (5-FU, 700 mg/m2/d) and folinic acid (FA, 300 mg/m2/d) combined with oxaliplatin (l-OHP, a nonnephrotoxic platinum complex, 25 mg/m2/d) were infused continuously for 5 days every 3 weeks. In a pilot randomized study, the infusion of all three drugs at a constant rate resulted in World Health Organization (WHO) Grade 3 or 4 toxicity in all four patients compared with no such toxicity in four patients if the infusion rate was modulated according to circadian rhythms. In this Phase II trial, drug delivery was modulated sinusoidally over the 24-hour day with peak flow rates at 4 AM for 5-FU and FA and at 4 PM for l-OHP, using an ambulatory programmable-in-time pump. All patients and 784 of 839 courses (93%) were evaluable for toxicity. Dose-limiting toxicities (WHO Grade 2 to 4) included diarrhea (19% of courses) and vomiting (35% of courses). In addition, WHO Grade 2 to 4 hematologic or mucosal toxicity, respectively, occurred in 2.5% and 7% of courses. Two toxic deaths were encountered. Peripheral sensory neuropathy led to discontinuation of l-OHP in 14 patients after 7 to 12 courses; it completely disappeared within 3 months. Fifty-four of the 93 patients had an objective response (58%; 95% confidence limits, 48% to 68%), irrespective of previous treatment or prior documented progression while receiving standard chemotherapy with 5-FU and FA or continuous 5-FU. Complete responses (CR) were seen in 6 patients (4 of which were proved histologically) and, after surgery, in 12 additional patients (overall CR rate, 18 of 93 [19%]; 95% confidence limits, 11% to 27%). Median progression-free survival (PFS) and overall survival were, respectively, 10 and 15 months, irrespective of prior therapy. Both PFS and survival were significantly longer in patients with a good performance status (PS, 0 or 1, by WHO criteria; respectively, 12 and 21 months) than in patients with poor PS (respectively, 8 and 10 months; P less than 0.01, by log-rank test). This chronopharmacologic protocol may have

Topics: Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Colorectal Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Infusion Pumps; Infusion Pumps, Implantable; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Remission Induction

5-Fluorouracil (5-FU) remains the most effective chemotherapeutic agent in the management of patients with metastatic colorectal cancer. Leucovorin enhances its efficacy, but also its toxicity. Cited data suggest modulation of 5-FU toxicity by high dose allopurinol. In a prospective randomized trial we assessed the ability of allopurinol in a conventional dose to modulate the toxicity of 5-FU-leucovorin combination without compromising its efficacy in 50 patients with advanced colorectal cancer. Twenty-seven patients were randomized for allopurinol but had no benefit in terms of response or reduced toxicity over the other 23. Survival of responders with colon cancer was longer than that of non-responders (p = 0.013). Although allopurinol failed to reduce 5-FU-leucovorin toxicity, it did not lower its expected efficacy.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies

The clinical course of 48 patients with low-risk metastatic gestational trophoblastic tumors (GTTs) treated with primary single-agent chemotherapy was reviewed. All patients achieved sustained remission, although 25 (51%) required a second single-agent regimen, and 7 (14%) needed combination chemotherapy to achieve it. An average of 3.4 courses of chemotherapy were necessary to achieve remission, and 6 patients (12%) underwent resection of resistant tumor foci. Primary single-agent chemotherapy is a reasonable treatment option in patients with low-risk metastatic GTT.

Topics: Aspartate Aminotransferases; Dactinomycin; Female; Granulocytes; Humans; Leucovorin; Methotrexate; Neoplasm Metastasis; Platelet Count; Pregnancy; Prognosis; Remission Induction; Trophoblastic Neoplasms; Uterine Neoplasms

17 patients with metastasizing colorectal cancer were treated in a phase II-study with systemic intravenous chemotherapy (Petrelli N, Proc ASCO 286, 1987) consisting of leucovorin 500 mg/m2 in a 2 hr infusion and 5-fluorouracil (5-FU) 600 mg/m2 bolus one hour after the commencement of the leucovorin infusion. Limiting toxicities were gastrointestinal, in form of nausea/vomiting of WHO grade 3 (n = 1) and of diarrhoea of maximal grade 4 (n = 5), as well as haematological with a maximal nadir of leucocytes of WHO grade 4 (n = 1) and of thrombocytes of WHO grade 1 (n = 1). Of the 14 evaluable patients an objective response was achieved in 21% of cases (CR: n = 1, PR: n = 2). 64% of the patients showed no change and 14% showed progression of their disease, 7 out of the 17 patients have died; the median survival was 24 months. With respect to objective remission, our result of 21% response rate is lower than the median of 32% of 24 different studies comprising 695 patients; nevertheless, the present response rate is within the range observed in the published studies of between 0% and 67%. In order to estimate the antitumoral efficacy of the new regimen 5-FU/leucovorin more objectively, a retrospective comparison of the therapy regimens used most frequently in disseminated colorectal cancer (5-FU monotherapy, 5-FU/methotrexate (MTX), 5-FU/MTX/low dose leucovorin, 5-FU/cisplatin, 5-FU/leucovorin) has been performed. The continuous administration of 5-FU monotherapy, with an objective response rate of 26%, was superior to standard 5-FU monotherapy as a bolus injection or short-term infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diarrhea; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Survival Analysis

A new combination of mitoxantrone, folinic acid (leucovorin), and infusional fluorouracil (5-FU) was administered to 57 previously treated patients with metastatic breast cancer to evaluate the response rate, response duration, and toxicity of this regimen. Fifty-three patients who received 313 courses of therapy were assessable for response and toxicity. Median age was 48 years (range, 33 to 80 years), and the patients had received an average of 1.5 chemotherapy regimens before this study. Of 53 assessable patients, 24 (45%, or 42% of all entered patients) experienced partial responses (PRs) with a median duration of 6 months (range, 2 to 13 months). Nine (69%) of 13 assessable patients without prior doxorubicin treatment responded, compared with 15 (38%) of 40 with prior doxorubicin (P less than .05). Toxicity was generally mild with dose reductions necessitated more often by mucositis and/or diarrhea than by myelosuppression. One patient with prior high-dose doxorubicin treatment developed congestive heart failure. The combination of mitoxantrone, leucovorin, and infusional 5-FU is an active and well-tolerated regimen for metastatic breast cancer and deserves further evaluation in patients without prior doxorubicin therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Survival Analysis

Between September 1988 and August 1990, we treated 35 women with metastatic breast cancer with a novel regimen containing mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin. This regimen was designed to take full advantage of the favorable toxicity profiles of these agents while maintaining a high level of activity. All patients had received previous chemotherapy (adjuvant only, 15 patients; at least one metastatic regimen, 20 patients). Seven patients had received previous doxorubicin, but none within 6 months of study entry. Of 31 assessable patients, 20 (65%) had objective responses (two complete, 18 partial), with a median response duration of 6 months (range, 3 to 16+ months). Four patients with bone metastases (abnormal bone scan only) and pain were not considered assessable by strict response criteria; two of these patients had sustained symptomatic relief for 6 and 8 months, respectively. Myelosuppression was the most frequent toxicity but was mild in most patients; only four hospitalizations for fever and neutropenia were required (2% of courses). No severe thrombocytopenia occurred and no RBC transfusions were required. Alopecia, mucositis, and nausea/vomiting were uncommon and were not severe in any patient. The combination of mitoxantrone, 5-FU, and high-dose leucovorin is well tolerated and active as a first- or second-line treatment for metastatic breast cancer. Comparison with other standard regimens for breast cancer is indicated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis

A phase I study of 5-fluorouracil 600 mg/m2/week and folinic acid 500 mg/m2/week on day 1 and cisplatin administered weekly on day 2 was carried out on 30 patients with metastatic colorectal carcinoma of which 20 patients were pretreated with 5-fluorouracil. The first group of patients received cisplatin at the dose of 5 mg/m2/week. Cisplatin was then escalated to 10, 15, 20, 25, 30, and 35 mg/m2/week for subsequent groups of patients. Gastrointestinal side-effects were the dose-limiting toxicity. A therapy related death was seen at the dose of 35 mg/m2/week of cisplatin. The maximally tolerated dose of cisplatin in combination with 5-fluorouracil and citrovorum factor is 20 mg/m2/week. The optimally tolerated dose of 5-fluorouracil is 400 mg/m2/week in modulation with citrovorum factor 500 mg/m2/week. The recommended doses for a phase II study are cisplatin 20 mg/m2/week, 5-fluorouracil 400 mg/m2/week, and citrovorum factor 500 mg/m2/week.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Colorectal Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Remission Induction

Twenty consecutive patients with advanced breast cancer were treated with a combination of cyclophosphamide 600 mg/m2 i.v. on day 1, epidoxorubicin 75 mg/m2 on day 1, and 5-fluorouracil 375 mg/m2 i.v. with folinic acid 200 mg/m2 i.v. on days 1----3. The overall response rate was 60%, with 10% of patients showing a complete response with a mean duration of 11.1 + months, and 50% of patients a partial response of 7.4 + months. A stabilization of 5.2 + months was obtained in 20% of cases, while 20% of patients progressed. The most frequently observed toxicity was leukopenia, while expected mucosal toxicities were rather mild.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Drug Evaluation; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Middle Aged; Neoplasm Metastasis; Remission Induction

Fifty-three patients with small cell carcinoma of the lung were treated with chemotherapy and radiotherapy, 40 Gy in the chest tumour. Intrathoracic failure occurred in 89% of the cases with extensive disease and in 60% of those with limited disease. Since 86% of all failures were localized within the target volume, one can conclude that in most cases the radiation dose was too low for eradication of the tumour. The treatment technique resulted in dose inhomogeneities of more than +/- 5% in 45% of the cases. The high local failure rate might indicate the need of improved radiotherapy, in the first place higher radiation dose. However, 82% of the patients with limited disease and local failure and 50% of those without local failure also developed distant metastases. This might indicate that the curative potential of improved thoracic radiotherapy probably is limited. Besides, lethal treatment toxicity affected particularly patients in whom local cure had been achieved, indicating the difficulty of increasing the treatment intensity without increasing the lethal toxicity in potentially curable cases.

Topics: Adult; Aged; Carcinoma, Small Cell; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Radiotherapy Dosage; Survival Analysis; Vincristine

A clinical trial was designed to find the maximally tolerated dose of weekly leucovorin (LV) that could be combined with 4 weeks of protracted infusion (PI) of 5-fluorouracil (5FU) at a fixed dose of 200 mg/m2. A total of 36 patients with disseminated gastrointestinal malignancies were treated; 9 either progressed or died before receiving 4 weeks of treatment leaving 27 patients evaluable for toxicity and response. 5FU was given as a protracted infusion using an ambulatory infusion pump and indwelling venous access. LV doses included 20, 25, 50, and 75 mg/m2 given as an i.v. push at the time of weekly pump fill with 5FU. In all, 72% of the patients tolerated LV at 20 mg/m2 for 4 continuous weeks, whereas the higher doses required treatment rests prior to 4 weeks. The dose-limiting toxicity at all doses was stomatitis. No significant myelosuppression was seen; diarrhea was infrequent. Overall, 40% of the patients with measurable cancer had partial responses. In view of evidence of biologic and therapeutic effects of these weekly doses of 20 mg/m2 LV with 200 mg/m2 5FU per day given as a protracted infusion over 4 weeks, phase II trials and multimodality studies for patients with gastrointestinal malignancies are being initiated at our institution using this dose and schedule.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

The efficacy and toxicity of leucovorin 500 mg/m2 administered intravenously (IV) over 30 minutes daily for five days followed in one hour by fluorouracil (5-FU) 375 mg/m2 administered IV daily for five days, each given every 3 weeks, was assessed in 54 previously treated patients with metastatic breast cancer. An overall objective response rate of 24% was achieved (95% confidence interval, 13% to 38%), with an additional 56% of patients maintaining stable disease. Eleven of 12 patients who responded had received previous 5-FU therapy. Toxicity of this regimen included grade 3 diarrhea in 13%, grade 3 or 4 mucositis in 33%, grade 3 or 4 granulocytopenia in 65%, and grade 3 or 4 thrombocytopenia in 19%. Delay of treatment was required for hematologic toxicity in 44 patients. Thirty-eight patients required dose reductions due to toxicity. Biochemical evaluation of tumor biopsy specimens obtained from 17 patients used as their own controls with and without leucovorin was performed. These studies reveal an increased stabilization of the 5-fluorodeoxyuridylate (FdUMP)-thymidylate synthase (TS) folate ternary complex with the addition of leucovorin. There was a 71% +/- 14% occupancy or inhibition of the enzyme with the use of both 5-FU and leucovorin, v 30% +/- 13% for 5-FU alone (P2 less than .037). The percent TS bound in responding patients was substantially higher than in those patients with progressive disease. Finally, the mean total tumor TS pre-therapy in seven patients was 31 fmol/mg compared with a mean of 81 fmol/mg in these same seven patients 24 hours after therapy. This 2.6-fold increase suggests that there is an induction of the enzyme, TS, with 5-FU treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Female; Fluorouracil; Humans; Leucovorin; Menopause; Middle Aged; Neoplasm Metastasis; Thymidylate Synthase

A prospectively randomized clinical trial was conducted to determine the therapeutic effect of five individual combination chemotherapy regimens compared to single agent FUra for the treatment of advanced colorectal cancer. For the purposes of this symposium, the detailed results of therapy will be presented only for PTS treated with FUra alone or FUra + LV* in a high dose (200 mg/m2) or a low dose (20 mg/m2) daily for five days. Two hundred twelve PTS were randomized to one these three regimens, and 208 PTS (98%) were available for analysis. Median time from randomization is 18 months and approximately 70% of PTS have died. Both LV* + FUra regimens are associated with significantly improved survival compared to single agent FUra (p less than or equal to 0.03). In addition, interval-to-tumor-progression, measurable tumor response rates, and measures of quality of life (performance status, weight gain, symptomatic relief) were also significantly improved with the addition of LV*. The most favorable regimen in the trial is low dose LV* + FUra based on considerations of both therapeutic results and cost. A national intergroup trial will examine the efficacy of the low dose LV* + FUra regimen in the surgical adjuvant setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Dose-Response Relationship, Drug; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Palliative Care; Random Allocation

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Random Allocation

Two trials of CF-FUra in patients with metastatic colorectal cancer were performed, both using a 3 day loading dose and then weekly maintenance doses to minimize toxicity. The first trial used CF by IV infusion with constant dose of FUra 400 mg/m2, and the second trial used oral CF with escalating doses of FUra. In the first trial, 45 eligible patients (20 with and 25 without prior therapy) were treated. Toxicity usually consisted of diarrhea or weakness and was controlled by delaying or decreasing 5FU dose. Subjective responses occurred in 75% of patients but did not correlate with antineoplastic effect. Objective responses were seen in 36% and stabilization of disease in 31% of patients, and correlated with prolonged survival. Median survival was 8 months for patients with prior treatment and 10 for those without, and 12 month survival was 32% and 40%, respectively. There was no correlation between the development of toxicity and response or survival. The second trial was recently conducted in cooperation with Duke University to determine toxicity and efficacy of oral CP with IV FUra prior to a randomized trial of this combination versus placebo with IV FUra. Eighteen patients were treated and serum levels of folates were obtained on 10. First toxicity occurred at FUra doses ranging from 375 to 850 mg/m2, and consisted of diarrhea in 9, lethargy in 7, nausea/vomiting in 4, dermatitis in 4, conjunctivitis in 2, hypersalivation in 2, stomatitis in 1, and profound granulocytopenia in 1. Response rate was 35% and stabilization was 35% with median survival of 14 months and 12 month survival of 56%.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Neoplasms; Prostatic Neoplasms

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Evaluation; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Colorectal Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

We determined the therapeutic effect of fluorouracil (5-FU) in combination with folinic acid (FA) in patients with measurable recurrent or metastatic carcinoma of the colon or rectum by comparing it to standard 5-FU therapy in a prospective randomized controlled trial. Patients were randomized to receive either FA, 200 mg/m2/d for five consecutive days, or nothing. All patients received 5-FU, 370 mg/m2/d for five days on the first course, with subsequent dose modifications to maintain equal toxicity in the two arms. One hundred thirty patients were entered on trial and only five were excluded from the analysis because they did not meet the eligibility criteria or they refused therapy after randomization. The two treatment arms were balanced for 11 clinical characteristics. Patients were evaluated for response at the end of every two treatment courses and toxicity after every course of therapy. Median follow-up was 1.45 years. Dose-limiting toxicity was mucositis and diarrhea on this treatment schedule, although neutropenia was apparent. The response rate was 33% (21 of 63 patients) in the 5-FU and FA arm and was 7% (four of 61 patients) in the 5-FU arm (P less than .0005). Time to disease progression was significantly different in the combination arm as compared with the single-agent arm (P = .023). Overall survival was significantly longer for patients treated with 5-FU and FA as compared with those receiving 5-FU alone (P = .05). The median survival was 12.6 months for patients receiving the combination, and 9.6 months for those receiving 5-FU alone. Our results indicate that the combination of 5-FU and FA is effective treatment for patients with metastatic or recurrent carcinoma of the rectum and colon who have not received prior chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Random Allocation; Rectal Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Colonic Neoplasms; Drug Synergism; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Methotrexate; Neoplasm Metastasis; Rectal Neoplasms

Experimental data show that sequencing methotrexate (MTX) and 5-fluorouracil (5-FU) may result in synergistic antitumor activity. Moreover, the effect of 5-FU is increased by folinic acid (FA), and finally, cyclophosphamide (CPA) produces an expansion of tumor growth fraction, suggesting an increased cytotoxic effect of cycle-specific drugs subsequently administered. Based on these premises, we have performed a Phase II study with CPA (600 mg/m2 i.v., day 1), MTX (200 mg/m2 1-h i.v. infusion, day 7), 5-FU (600 mg/m2 i.v., day 8), and FA (500 mg/m2 2-h i.v. infusion, day 8 plus 15 mg p.o. every 6 h on days 8 and 9) administered every 3 weeks. Thirty-six patients with metastatic breast cancer were admitted into the study. Median age was 52 years, and all but two patients were postmenopausal. Dominant sites of metastases were soft tissues in 10 patients, bones in 7 patients, and viscera in 19 patients. All patients were pretreated with chemo- and/or hormone therapy. Sixteen patients achieved an objective response (44.5%: 1 complete response and 15 partial responses), 8 had stable disease (SD) (22.2%), and 12 progressed (33.3%). Twenty-one patients had previously received conventional CMF in an adjuvant setting (15 patients) or for metastases (6 patients): 1 complete response (CR) and 7 partial responses (PR) were obtained in the first group and 1 in the second. Major toxic effects were hair loss (56.4%), nausea and vomiting (72%), mucositis (52.5%), and leukopenia (61%). A randomized study could be useful to assess the role of sequential CMF versus conventional CMF in metastatic breast cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Synergism; Female; Fluorouracil; Humans; Leucovorin; Methotrexate; Middle Aged; Neoplasm Metastasis; Time Factors

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Doxorubicin; Extremities; Humans; Leucovorin; Methods; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Prognosis; Prostheses and Implants; Random Allocation

Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospectively controlled study comparing high-dose infusion methotrexate with leucovorin against standard-dose methotrexate without leucovorin. Patients were stratified for prior treatment and hematogenous metastases prior to randomization. Patients received either methotrexate (1,500 mg/m2) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly. Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity. After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly. One patient was ineligible and four had inadequate follow-up to assess response (less than two weeks). Forty-two patients were evaluable for survival and 37 for response. Six of 19 patients (32%) treated with high-dose infusion responded (one complete response) and four of 18 patients (22%) receiving standard dosage responded (P = .52). Treatment with high-dose methotrexate resulted in an improved duration of disease control over standard dosage with the respective median times to progression of 11 weeks and five weeks (P = .04). These differences were most marked in good performance status patients (P = .007) and those without hematogenous dissemination (P = .02). Toxicity, however, was also significantly worse in the high-dose treatment group (P = .01) and survival was identical between treatments (4.2 months). The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival. Good performance status patients may benefit from more aggressive therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Injections, Intramuscular; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Prognosis; Random Allocation

Fifty-three patients with metastatic osteogenic sarcoma were treated with vincristine, high-dose methotrexate with citrovorum factor rescue, and cisplatin. Metastases were surgically removed in most patients, either prior to chemotherapy or following initial response to therapy. Among 29 previously treated patients, responses to initial chemotherapy included two complete remissions, six partial remissions, and eight patients with stable disease. Twenty-three patients were disease-free, six for greater than 12 months. Toxicity was moderate, but usually reversible. There were two toxic deaths and one unexplained death 48 hours following a dose of cisplatin.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Kidney Diseases; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Neutropenia; Osteosarcoma; Thrombocytopenia; Time Factors; Vincristine

In order to determine whether combination chemotherapy offered any advantage over single-agent therapy in cases of metastatic non-small cell bronchogenic carcinoma, we performed a randomized study in 56 patients comparing combination chemotherapy (cyclophosphamide, doxorubicin, methotrexate, procarbazine, leucovorin--CAMP-L) with a regimen in which the same drugs were given sequentially (methotrexate/leucovorin followed by cyclophosphamide/doxorubicin at progression). Of the patients receiving the combination, 52% (14 of 27) had either a partial response or stable disease, compared to 17% (5 of 29) in the sequential group. Of the patients with adenocarcinoma, those in the combination group had a significantly longer survival than those treated in the sequential group (medians, 10.0 vs 2.8 months; P less than 0.01); such a difference could not be demonstrated for patients with squamous carcinoma. Patients who achieved a partial response had a median survival of 15.3 months; those with stable disease survived a median of 10.0 months; and those with no response survived a median of 2.5 months (P less than 0.0001). Four patients died from chemotherapy-related complications: three from methotrexate toxicity and resultant infection and one from pneumonia associated with neutropenia. We conclude that the short survival of non-responding patients and the survival benefit accompanying response or stabilization make early aggressive combination therapy useful for patients with metastatic non-small cell lung cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Clinical Trials as Topic; Cyclic AMP; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Procarbazine

A randomized prospective clinical trial involved 259 cases of advanced recurrent Stage III and IV epidermoid cancers of the head and neck. The cases were randomized among three treatment programs evaluating two dose schedules and a combination treatment of methotrexate. The treatments consisted of: weekly methotrexate, biweekly methotrexate with leucovorin rescue (ML), and biweekly ML combined with cyclophosphamide and cytosine arabinoside (MLCC). Equivalent overall drug-related toxicity was produced with a 5% drug-related fatality rate. Methotrexate alone produced significantly more skin and mucosal toxicity, and the combination (MLCC) resulted in more hematologic toxicity than other treatments. Complete and partial objective responses were achieved in 26%, 24%, and 18% by each treatment. Methotrexate alone produced a median duration of response and 105 days compared with 42 and 49 days from the other treatments. Duration of response was significantly longer and survival was better in the methotrexate-alone group. Response was markedly stage dependent; 40% of Stage III patients achieved response, whereas only 17% of Stage IV patients responded. Presence of visceral metastases decreased response rates and the likelihood of response was particularly compromised by pulmonary metastatic spread; only seven of 54 such patients responded. Decreased survival was related to non-ambulatory performance status, disease-free intervals of less than one year and weight loss. Survival differences between Stage III and IV patients could not be shown. This study demonstrates the therapeutic superiority of weekly i.v. treatment with methotrexate but failed to support claims of an improved therapeutic index for high-dose methotrexate with leucovorin rescue. As the only randomized prospective clinical trial of chemotherapy in advanced head and neck cancer, this study reinforces the weekly i.v. schedule of methotrexate as the standard against which other drug schedules and drug combinations should be compared.

Topics: Adult; Aged; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Prognosis; Prospective Studies

We have conducted a Phase 1 study of aminopterin (AMT) with leucovorin (LV) in 17 patients. AMT was administered by bolus injection every 7 to 14 days in dosages from 25 to 425 mg/sq m. LV rescue was instituted at 24 hr and continued for 48 to 72 hr. At dosages above 50 mg/sq m, we observed nephrotoxicity defined as greater than or equal to a 25% increase in serum creatinine 24 hr after AMT administration, but its incidence was not strictly dose related. Urinary alkalinization and volume expansion appeared to reduce the incidence of nephrotoxicity. Nephrotoxic drug courses were associated with 24-hr plasma AMT levels [3.6 +/- 2.0 (S.D.) X 10(-6) M] which were significantly higher than nonnephrotoxic courses (1.6 +/- 1.0 x 10(-6) M) (p less than 0.05). In nonnephrotoxic courses, serum elimination pharmacokinetics appeared to be biphasic with a t1/2 alpha of 1.08 +/- 0.01 hr and t1/2 beta of 12.31 +/- 0.06 hr. Systemic toxicity (myelosuppression and mucositis) could be prevented in patients with impaired AMT clearance by the administration of LV at an increased dose rate. In several courses, systemic toxicity occurred in spite of apparently normal plasma clearance, suggesting that 24-hr plasma levels may not accurately reflect intracellular drug effects. Cytokinetic studies on bone marrow aspirates allowed determination of the rescue effect of LV and may prove useful in predicting marrow protection.

Topics: Aminopterin; Bone Marrow; Clinical Trials as Topic; Drug Administration Schedule; Humans; Kidney; Leucovorin; Leukopenia; Methotrexate; Neoplasm Metastasis; Neoplasms; Solubility

A randomized trial comparing Vincristine, Adriamycin, Cyclophosphamide (VAC) with or without Methotrexate with citrovorum factor rescue (VACM) was performed in 64 patients with metastatic postmenopausal mammary carcinoma. Previous treatment of metastases, dominant site of metastases and performance condition were similar in the patients. No significant difference was found in the response rates (complete remission + partial remission; VAC 21/31, VACM 25/33), in the duration of the remissions or in the survivals. The duration of remission in CR was significantly longer than in PR. No serious side effects were observed. The VAC regimen is preferable, particularly with respect to the costs and the simple procedure of administration.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Lymphatic Metastasis; Menopause; Methotrexate; Middle Aged; Neoplasm Metastasis; Prognosis; Random Allocation; Vincristine

Since January 1974, 95 patients with anterior tongue and floor of the mouth cancers were included in a randomized trial. After stratification according to staging and initial treatment, one-third of the patients received chemotherapy for 2 years (methotrexate 400 mg followed by citrovorum factor 100 mg + bleomycin 60 mg/week, during the first 15 weeks), one-third of the patients received immunotherapy with weekly C. parvum injections during 2 years, while the remaining third did not receive any treatment. If adjuvant treatment seems to delay recurrence it did not significantly decrease the recurrence rate. Survival is also not signigicantly modified by adjuvant treatment and was better for patients with small tumors. Patients who previously received radiotherapy did not benefit from adjuvant therapy.

Topics: Antigens, Bacterial; Bleomycin; Carcinoma, Squamous Cell; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Mouth Floor; Mouth Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Propionibacterium acnes; Random Allocation; Tongue Neoplasms

Topics: Adolescent; Bone Neoplasms; Clinical Trials as Topic; Doxorubicin; Drug Therapy, Combination; Extremities; Female; Humans; Joint Prosthesis; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Vincristine

Topics: Adolescent; Adult; Bone Neoplasms; Child; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Time Factors; Vincristine

Twenty-nine evaluable patients with nonmetastatic osteosarcoma were given sequential combination chemotherapy utilizing high-dose methotrexate with citrovorum factor rescue, vincristine, adriamycin, and cyclophosphamide. Fourteen (48%) of 29 patients are currently disease-free for 8--48 months from initiation of chemotherapy with a median disease-free survival of 21 months. The projected 4-year disease-free survival is 13%. At 4 years the projected overall survival is 57%. In this particular study, adjuvant chemotherapy does not appear to significantly prevent the development of overt metastases. In four patients, delayed onset of metastasis was observed at 18--43 months from initiation of treatment.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Vincristine

Topics: Child; Clinical Trials as Topic; Humans; Infusions, Parenteral; Leucovorin; Methotrexate; Neoplasm Metastasis; Neuroblastoma

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Agents; Bone Neoplasms; Cell Division; Child; Clinical Trials as Topic; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Prognosis; Radiotherapy, High-Energy; Time Factors

Topics: Amputation, Surgical; Bone Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Femoral Neoplasms; Follow-Up Studies; Humans; Injections, Intramuscular; Injections, Intravenous; Leucovorin; Lung Neoplasms; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Time Factors; Vincristine

The second-line chemotherapy in metastatic colorectal cancer (mCRC) with FOLFIRI-aflibercept demonstrated an increase in survival compared with FOLFIRI in patients previously treated with oxaliplatin-based regimens. Few data are available in patients treated previously with bevacizumab. Our objective is to evaluate the efficacy and safety of FOLFIRI-aflibercept in second-line treatment in patients who have previously received bevacizumab.. This is a observational, retrospective study of patients with mCRC treated with FOLFIRI-aflibercept in 2nd line in eight hospitals in the Valencian Community. Survival, response, and toxicity were analyzed.. 122 patients with a median age of 61 years were included. 89% of patients had PS 0-1. The median of PFS (progression free survival) and OS (overall survival) was 5.45 (95% CI 4.74-6.15 months) and 10.15 (95% CI 7.47-12.82 months), respectively. Disease control rate 59.8%. The most common grade 3-4 adverse events were neutropenia (13,1%) and asthenia (9%). The presence of hypertension during treatment with FOLFIRI-aflibercept was associated with a survival benefit. Median of OS was 14.45 (95% CI 11.58-17.32) in patients with hypertension vs 7.78 (95% CI 5.02-10.54) in patients without hypertension (p = .001). Our results suggest that the presence of PS 0, primary tumor surgery, metachronous metastases, and the presence of only 1 metastatic location, are favorable prognostic factors associated with better OS.. Our results confirm the value of maintaining angiogenesis inhibition with FOLFIRI-aflibercept in mCRC after progression to a first-line treatment with bevacizumab. The development of hypertension during treatment is a possible predictive marker of response.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Hypertension; Leucovorin; Middle Aged; Neoplasm Metastasis; Recombinant Fusion Proteins; Rectal Neoplasms; Retrospective Studies

Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy.. This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants.. Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006).. Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Lung Neoplasms; Neoplasm Metastasis; Prognosis; Rectal Neoplasms; Retrospective Studies; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Oxaliplatin

A retrospective study was conducted to analyze which translational therapy, palliative chemotherapy and surgery is the best treatment for locally advanced and advanced pancreatic cancer, and to screen out the dominant population for the best treatment. A total of 83 patients with pancreatic cancer, including locally advanced and advanced pancreatic cancer, who had lost the opportunity for radical surgery and were admitted to Zhejiang Provincial People's Hospital between January 2015 and July 2021 were collected. A total of 39 patients received palliative chemotherapy, 25 patients received conversion therapy and 19 patients tried surgery at the first visit. We conducted survival follow-up and prognostic evaluation of 83 patients. The median overall survival (mOS) and median progression-free survival (mPFS) of 25 pancreatic cancer patients who received conversion therapy were longer than those of pancreatic cancer patients who received palliative chemotherapy (mOS: 16 months vs. 9 months, P = 0.001; mPFS: 11 months vs. 7.5 months, P = 0.038) and surgery (mOS: 16 months vs. 9 months, P = 0.018; mPFS: 11 months vs. 5.5 months, P < 0.001). Multivariate and Kaplan-Meier analysis showed that age, distant metastasis, and the degree of CA199 declined after chemotherapy were independent factors affecting overall survival (OS) of pancreatic cancer patients who received conversion therapy. Conversion therapy can improve OS and progression-free survival in patients with locally advanced or advanced pancreatic cancer to a certain extent. Some patients with advanced pancreatic cancer have surprising results after receiving conversion therapy.

Topics: Age Factors; Aged; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oxaliplatin; Palliative Care; Pancreatic Neoplasms; Progression-Free Survival; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Quality-Adjusted Life Years

To evaluate and compare the efficacy and safety of bevacizumab and aflibercept in second-line treatment in metastatic colorectal cancer (mCRC) in real-life clinical practice.. Retrospective observational study of patients treated with second-line bevacizumab (BFIR) and aflibercept (AFIR) in mCRC, associated with a FOLFIRI scheme, in the last 12 years (January 2009-January 2021) in a tertiary hospital. Patients with prior oxaliplatin-based treatment were included.. previous chemotherapy, treatment time (TT), progression-free survival (PFS), overall survival (OS). To assess toxicity, adverse effects that caused delay in cycle administration were recorded. The lost cycles/month of treatment (CP/MT) were also calculated.. Eighty-four patients [40 (47.6%) AFIR and 44 (52.4%) BFIR]. Average age: 60.2 ± 10.7 years. In 79.8% the previous scheme was FOLFOX type. Efficacy of AFIR vs BFIR: median HR of TT (95% CI) = 0.816 (0.527-1.266); p = 0.365, PFS HR (95% CI) = 0.674 (0.389-1.117); p = 0.159, OS HR (95% CI) = 0.566 (0.342-0.936); p = 0.026. The main reason for the delay in administration was neutropenia (28.7% AFIR vs 24.7% BFIR), and the greatest difference found was thrombopenia (13.9% AFIR vs 2.5% BFIR), without observing large differences between the rest of adverse reactions. Mean CP/MT: 0.49 ± 0.46 cycles with AFIR and 0.33 ± 0.27 with BFIR; p = 0.046.. Although no statistically significant differences have been found in TT or PFS, it would be more advisable to use BFIR scheme due to its better results in OS and toxicity profile.. OBJETIVO: Evaluar y comparar la eficacia y seguridad de bevacizumab y aflibercept en segunda línea de tratamiento en el cáncer colorrectal metastásico (CCRm) en la práctica clínica real. MéTODOS: Estudio observacional retrospectivo de los pacientes tratados con bevacizumab (BFIR) y aflibercept (AFIR) en segunda línea en CCRm, asociado a un esquema FOLFIRI, en los últimos 12 años (septiembre 2009-enero 2021) en un hospital de tercer nivel. Se incluyeron pacientes con tratamiento previo basado en oxaliplatino. Variables medidas: esquema previo, tiempo de tratamiento (TT), supervivencia libre de progresión (SLP), supervivencia global (SG). Para valorar toxicidad, se registraron los efectos adversos que provocaron retraso en la administración del ciclo. También se calcularon los ciclos perdidos/mes de tratamiento (CP/MT).. 84 pacientes [40 (47,6%) AFIR y 44 (52,4%) BFIR]. Media de edad: 60,2 ± 10,7 años. En el 79,8% el esquema previo fue tipo FOLFOX. Eficacia de AFIR vs BFIR: HR de mediana de TT (IC95%) = 0,816 (0,527–1,266); p = 0,365, HR de SLP (IC95%) = 0,674 (0,389–1,117); p = 0,159, HR de SG (IC95%) = 0,566 (0,342–0,936); p = 0,026. El principal motivo de retraso en la administración fue neutropenia (28,7% AFIR vs 24,7% BFIR), y el que más diferencia hubo entre ambos la trombopenia (13,9% AFIR vs 2,5% BFIR), sin observarse grandes diferencias entre el resto de reacciones adversas. Media de CP/MT: 0,49 ± 0,46 ciclos con AFIR y 0,33 ± 0,27 con BFIR; p = 0,046.. Aunque no se han encontrado diferencias estadísticamente significativas en TT ni en SLP, sería más recomendable utilizar el esquema BFIR por sus mejores resultados en SG y perfil de toxicidad.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Progression-Free Survival; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retrospective Studies

Some patients with cancer may present with progressive or persistent disease at a limited number of sites following a period of treatment response. We evaluated the safety and effectiveness of metastasis-directed radiotherapy (MRT) for oligoprogressive or oligopersistent disease in patients receiving systemic treatment for metastatic colorectal cancer (mCRC).. Patients with mCRC who received 5-fluorouracil, leucovorin, and oxaliplatin; 5-fluorouracil, leucovorin, and irinotecan; and/or capecitabine chemotherapy between 2011 and 2020 at a single institution were identified. Then, those who underwent MRT for five or fewer lesion sites while receiving systemic treatment for other metastases were categorized. The primary endpoint was time to change to systemic therapy. Secondary endpoints included MRT-related toxicity, overall survival, and local control.. Among 4157 patients included, 91 (2%) received MRT to limited lesion sites (55 oligoprogressive and 36 oligopersistent) during systemic treatment following a period of treatment response. The median time to change to next-line systemic therapy was 5 months in the overall cohort (measured from the current chemotherapy session) and 9.5 (range, 6.0-40.6) months in the MRT group (measured from the MRT session). No severe toxicity or systemic treatment interruption was observed following MRT. The 1-year local control and overall survival rates were 69% and 99%, respectively.. In patients with oligoprogressive or oligopersistent mCRC, MRT may be performed safely in conjunction with systemic treatment to maximize the benefit of systemic therapy and to prolong the time to change to systemic therapy. Further prospective studies should confirm these findings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Prospective Studies; Rectal Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Neoplasm Metastasis

To compare the efficacy and safety of folinic acid, fluorouracil and irinotecan (FOLFIRI) plus bevacizumab or aflibercept in metastatic colorectal cancer (mCRC) patients pretreated with oxaliplatin-based chemotherapy.. We analysed the treatment outcomes of patients receiving FOLFIRI in combination with bevacizumab or aflibercept as second-line treatment for mCRC between October 2017 and March 2020. This analysis included 67 patients receiving FOLFIRI plus aflibercept and 83 receiving FOLFIRI plus bevacizumab.. The overall response rate (ORR) was 13.6% (95% confidence interval 4.85-22.34) in the FOLFIRI-aflibercept group and 14.7% (95% confidence interval 6.68-22.71) in the FOLFIRI-bevacizumab group. This difference in ORR was not statistically significant. The median progression-free survival was 8.6 months in the FOLFIRI-bevacizumab group and 8.5 months in the FOLFIRI-aflibercept group (P = 0.752). Patients in the FOLFIRI-bevacizumab group showed a median overall survival of 12.4 months, whereas patients in the FOLFIRI-aflibercept group had a median overall survival of 13.7 months (P = 0.276). There were no significant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRI-aflibercept group.. FOLFIRI plus bevacizumab and FOLFIRI plus aflibercept had similar anti-tumour activities and toxicity profiles when used as second-line therapy in mCRC patients. Based on these data, both aflibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Rectal Neoplasms

The addition of anti-angiogenic agents to cytotoxic agents to improve outcomes has become the standard treatment for metastatic colorectal carcinoma. In this study, we evaluated the safety of bevacizumab plus FOLFIRI with that of ramucirumab plus FOLFIRI in second- and later-line treatment in Japanese patients with metastatic colorectal carcinoma. Patients who received ramucirumab or bevacizumab as a second- and later-line treatment between January 2016 and March 2020 were included. Treatment regimens, body surface area, dosage, number of treatment courses, and adverse events( AEs) were evaluated. There were 66 and 17 patients in the bevacizumab plus FOLFIRI and ramucirumab plus FOLFIRI groups, respectively. All patients developed AEs. AEs of grade 3/4 were documented in 84.8% and 100% of the patients in the bevacizumab plus FOLFIRI and ramucirumab plus FOLFIRI groups, respectively. Progressive disease was the most common reason for treatment discontinuation in both groups. Twelve (18.2%) and 5 (29.4%) patients in the bevacizumab plus FOLFIRI and ramucirumab plus FOLFIRI groups, respectively, discontinued treatment due to AEs. The most common AEs leading to discontinuation were malaise and decreased performance status. The findings of our study indicated that both bevacizumab plus FOLFIRI and ramucirumab plus FOLFIRI groups have a high incidence of AEs, and that medical professionals need to be aware of the frequent development of malaise and decreased performance status.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Japan; Leucovorin; Neoplasm Metastasis; Ramucirumab

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis

We aimed to compare the efficacy and the safety of the FOLFOX and the FLOT regimens in metastatic gastric cancer (mGC) as first-line treatment. It was a retrospective multicenter observational study. The comparisons between groups were conducted in terms of progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and hematologic adverse events. Seventy-nine patients, diagnosed with mGC between March 2012 and December 2019, treated with FOLFOX (n = 43) or FLOT (n = 36) regimens as first-line treatment were included in the study. The mPFS was 10.9 months [95% confidence interval (CI), 5.8-16.1] in the FLOT arm and 7.1 months (95% CI, 5.1-9.1) in the FOLFOX arm (P < 0.001). The ORR was 63.9% in the FLOT arm and 30.2% in the FOLFOX arm (P = 0.003). The mOS was 13.3 months (95% CI, 11.3-15.4) in the FLOT arm and 10.9 months (95% CI, 8.2-13.5) in the FOLFOX arm (P = 0.103). The hematologic adverse events in all grades were 88.4% (n = 38) in the FOLFOX arm compared with 80.6% (n = 29) in the FLOT arm (P = 0.335). The FLOT regimen might be a preferred option in mGC with an improved PFS and ORR compared with the FOLFOX regimen.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Esophagogastric Junction; Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Stomach Neoplasms; Survival Analysis

p130 Crk-associated substrate (p130Cas) is associated with poor prognosis and treatment resistance in breast and lung cancers. To elucidate p130Cas functional and clinical role in colorectal cancer (CRC) progression/therapy resistance, we performed cell culture experiments and bioinformatic/statistical analyses of clinical data sets. p130Cas expression was associated with poor survival in the cancer genome atlas (TCGA) data set. Knockdown/reconstitution experiments showed that p130Cas drives migration but, unexpectedly, inhibits proliferation in CRC cells. TCGA data analyses identified the growth factor epiregulin (EREG) as inversely correlated with p130Cas. p130Cas knockdown and simultaneous EREG treatment further enhanced proliferation. RNA interference and EREG treatment experiments suggested that p130Cas/EREG limit each other's expression/activity. Inverse p130Cas/EREG Spearman correlations were prominent in right-sided and earlier stage CRC. p130Cas was inducible by 5-fluorouracil (5-FU) and FOLFIRI (folinic acid, 5-FU, irinotecan), and p130Cas and EREG were upregulated in distant metastases (GSE121418). Positive p130Cas/EREG correlations were observed in metastases, preferentially in post-treatment samples (especially pulmonary metastases). p130Cas knockdown sensitized CRC cells to FOLFIRI independent of EREG treatment. RNA sequencing and gene ontology analyses revealed that p130Cas is involved in cytochrome P450 drug metabolism and epithelial-mesenchymal transition. p130Cas expression was associated with poor survival in right-sided, stage I/II, MSS (microsatellite stable), or BRAF-mutated CRC. In summary, p130Cas represents a prognostic factor and potential therapeutic target in CRC.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Atlases as Topic; Breast Neoplasms; Camptothecin; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Crk-Associated Substrate Protein; Epiregulin; Epithelial-Mesenchymal Transition; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Gene Ontology; Humans; Leucovorin; Male; Middle Aged; Molecular Sequence Annotation; Mutation; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Proto-Oncogene Proteins B-raf; RNA, Small Interfering; Signal Transduction; Survival Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

Colorectal cancer is one of the most common cancers in the world. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor which provides survival benefit when combined with chemotherapy in RAS wild type metastatic colorectal cancer. Cutaneous toxicities associated with cetuximab have a significant impact on patient quality of life, treatment continuation and healthcare resource utilization.. A 60-year-old male patient presented with fatigue, weight loss and abdominal pain. Two closely located malignant polypoid lesions were detected in the sigmoid colon, and pathological examination revealed colonic adenocarcinoma.. The most common and earliest skin toxicity is acneiform rash which affects 60 to 80% of the patients. In this case, cetuximab-related severe acneiform rash was effectively treated by topical aloe vera. Topical aloe vera may be used in the management of cetuximab-related cutaneous toxicities without any side effect.

Topics: Acneiform Eruptions; Adenocarcinoma; Administration, Topical; Aloe; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Polyps; Colorectal Neoplasms; Disease Progression; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Skin Cream; Treatment Outcome

Nab-paclitaxel (Abraxane®) plus gemcitabine (AG) and Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) have shown significant clinical benefit and been widely used as 1. Markov model was developed with a lifetime survival projection in Microsoft Excel® to simulate the progression of the mPC over time. The quality-adjusted life years (QALYs), resource consumption in the health care sector and incremental cost-effectiveness ratios (ICERs) were reported. Uncertainty was assessed by one-way and probabilistic sensitivity analyses.. AG regimen provided an effectiveness of 1.35 QALY at an average cost of USD 22,300 whereas FOLFIRINOX regimen brought 0.82 QALY at a cost of USD 22,980 in lifetime horizon. Therefore, AG regimen was dominant with an ICER of USD -1300 compared with FOLFIRINOX regimen. AG arm generated less drug cost, medical cost, hospitalization cost, and end-of-life cost than FOLFIRINOX arm did. Sensitivity analyses confirmed the robustness of base case findings.. AG is likely a cost-effective option for the 1

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; China; Cost-Benefit Analysis; Deoxycytidine; Disease Progression; Fluorouracil; Gemcitabine; Health Care Costs; Hospitalization; Humans; Irinotecan; Leucovorin; Markov Chains; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Quality-Adjusted Life Years; Survival Rate

Anti-vascular endothelial growth factor (VEGF) agents have shown clinical benefits against metastatic colorectal cancer (mCRC) when combined with cytotoxic chemotherapeutic drugs. Because randomized controlled trials have restrictive enrollment criteria, and because the participants typically do not resemble actual patients, we here investigated the efficacy of bevacizumab as part of a combination therapy for mCRC in a Korean real-world practice setting.. We retrospectively evaluated 3748 patients with an initial diagnosis of mCRC or recurrent colorectal cancer with distant metastasis who received first-line chemotherapy in a tertiary cancer center. The primary study endpoint was overall survival. We used multivariate analysis using the Cox regression hazard model and propensity score matching (PSM) methods to adjust for any confounding clinicopathologic factors. Subgroup analysis was also performed for patients who did not receive local treatments for metastatic lesions before receipt of first-line chemotherapy.. In an initial crude analysis, patients who received first-line FOLFOX or FOLFIRI showed better survival outcomes if these regimens were combined with bevacizumab (median overall survival, 3.5 vs. 2.3 years; hazard ratio [HR] = 0.66; 95% confidence interval [CI], 0.59-0.73; P < .001). However, Cox regression hazard model adjusted analysis using PSM methods revealed no significant survival differences between these groups (3.0 vs. 2.6 years; HR = 0.92; 95% CI, 0.79-1.07; P = .2612). We performed further survival analysis of 2814 patients with unresectable disease without metastasectomy who received metastatic radiofrequency ablation before chemotherapy. Cox regression and PSM analysis indicated that bevacizumab group showed better survival (HR = 0.82; 95% CI, 0.71-0.94; P = .005; and HR = 0.84; 95% CI, 0.71-0.99; P = .018).. The addition of bevacizumab to a first-line chemotherapeutic regimen provides survival benefits in a real-world setting for mCRC patients who cannot undergo curative-intent local treatment for metastatic lesions.

Topics: Adult; Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies

Three vascular endothelial growth factor (VEGF) inhibitors, Bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are widely used for metastatic colorectal cancer (mCRC) patients who are treated with second-line chemotherapy. The difference in outcome between the three drugs has not been evaluated. In contrast to epidermal growth factor receptor inhibitors, VEGF inhibitors have few candidate predictors of efficacy.. Consecutive mCRC patients who were treated with second-line chemotherapy were retrospectively enrolled. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Subgroup analyses of prognostic and predictive efficacy markers were performed.. A total of 119 (41.2%), 107 (37.0%), and 63 patients (21.8%) were treated with FOLFIRI +BEV, RAM, or AFL, respectively. ORR, PFS, and OS showed no significant differences between three groups. However, the frequency of grade 3 or 4 adverse events (AEs) in the FOLFIRI +AFL group was significantly higher than that in the other groups (p < 0.001). Patients with grade 3 or 4 AEs, especially hypertension and neutropenia within the first four cycles of treatment had significantly longer PFS and OS than those without AEs, irrespective of treatment with VEGF inhibitors (p < 0.001). PFS in patients without prior BEV exposure was also significantly longer than that in patients with prior BEV exposure (p = 0.003).. Chemotherapeutic efficacy did not differ between the groups. Grade 3 or 4 AEs within the first four cycles of treatment and prior BEV exposure may be an effective predictor of treatment efficacy in mCRC patients administered VEGF inhibitors as second-line chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Hypertension; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Prognosis; Ramucirumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retrospective Studies; Survival Rate; Vascular Endothelial Growth Factor A

Panitumumab and cetuximab are monoclonal antibodies known to be effective in metastatic colorectal cancer (mCRC). Although the survival benefits when combined with chemotherapy have been determined, there are no studies comparing the two agents with chemotherapy in the second-line treatment. In this study, we aimed to compare the efficacy of cetuximab vs panitumumab in patients who previously received chemotherapy. Who progressed after first-line treatment for K-ras wild type mCRC were analyzed. The efficacy of cetuximab vs panitumumab on overall survival (OS) and progression-free survival (PFS) when combined with FOLFIRI regimen was compared retrospectively. Median PFS was 6.9 months in the cetuximab group and 4.7 months in the panitumumab group. Median OS cetuximab and panitumumab groups were 18.4 and 12.2 months, respectively. In the second-line treatment of K-ras wild type mCRC, both PFS and OS were found to be longer in patients receiving cetuximab than in patients receiving panitumumab, but no statistically significant difference was found.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Panitumumab; Proto-Oncogene Proteins p21(ras); Survival Analysis

FOLFOX is a combinational regimen of folinic acid (FnA, FOL), fluorouracil (5-Fu, F) and oxaliplatin (OxP, OX), and has been long considered as the standard treatment of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Recent developments of nano delivery systems have provided profound promise for improving anticancer efficacy and alleviating side effects of FOLFOX. Previously, a nanoformulation (termed Nano-Folox) containing OxP derivative and FnA was developed in our laboratory using nanoprecipitation technique. Nano-Folox induced OxP-mediated immunogenic cell death (ICD)-associated antitumor immunity, which significantly suppressed tumor growth in the orthotopic CRC mouse model when administrated in combination with free 5-Fu.. A nanoformulation (termed Nano-FdUMP) containing FdUMP (5-Fu active metabolite) was newly developed using nanoprecipitation technique and used in combination with Nano-Folox for CRC and HCC therapies.. Synergistic efficacy was achieved in orthotopic CRC and HCC mouse models. It resulted mainly from the fact that Nano-FdUMP mediated the formation of reactive oxygen species (ROS), which promoted the efficacy of ICD elicited by Nano-Folox. In addition, combination of Nano-Folox/Nano-FdUMP and anti-PD-L1 antibody significantly inhibited CRC liver metastasis, leading to long-term survival in mice.. This study provides proof of concept that combination of two nano delivery systems can result in successful FOLFOX-associated CRC and HCC therapies. Further optimization in terms of dosing and timing will enhance clinical potential of this combination strategy for patients.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Hepatocellular; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; Drug Compounding; Drug Synergism; Female; Fluorodeoxyuridylate; Fluorouracil; Immunogenic Cell Death; Immunotherapy; Leucovorin; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Organoplatinum Compounds; Reactive Oxygen Species; Tissue Distribution

An upgraded understanding of factors (sex/estrogen) associated with survival benefit in advanced colorectal carcinoma (CRC) could improve personalised management and provide innovative insights into anti-tumour mechanisms. The aim of this study was to assess the efficacy and safety of cetuximab (CET) versus bevacizumab (BEV) following prior 12 cycles of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus BEV in postmenopausal women with advanced KRAS and BRAF wild-type (wt) CRC.. Prospectively maintained databases were reviewed from 2013 to 2017 to assess postmenopausal women with advanced KRAS and BRAF wt CRC who received up to 12 cycles of FOLFOXIRI plus BEV inductive treatment, followed by CET or BEV maintenance treatment. The primary endpoints were overall survival (OS), progression-free survival (PFS), response rate. The secondary endpoint was the rate of adverse events (AEs).. At a median follow-up of 27.0 months (IQR 25.1-29.2), significant difference was detected in median OS (17.7 months [95% confidence interval [CI], 16.2-18.6] for CET vs. 11.7 months [95% CI, 10.4-12.8] for BEV; hazard ratio [HR], 0.63; 95% CI, 0.44-0.89; p=0.007); Median PFS was 10.7 months (95% CI, 9.8-11.3) for CET vs. 8.4 months (95% CI, 7.2-9.6) for BEV (HR, 0.67; 95% CI 0.47-0.94; p=0.02). Dose reduction due to intolerable AEs occurred in 29 cases (24 [24.0%] for CET vs. 5 [4.8%] for BEV; p< 0.001).. CET tends to be superior survival benefit when compared with BEV, with tolerated AEs.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Middle Aged; Mutation; Neoplasm Metastasis; Oxaliplatin; Postmenopause; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Retrospective Studies; Survival Rate

We compared the efficacy and safety of second-line FOLFIRI with bevacizumab (Bmab) or aflibercept (AFL) in patients with unresectable metastatic colorectal cancer (mCRC) to clarify selection criteria for anti-angiogenic agents.. The subjects were patients with mCRC who received second-line FOLFIRI in combination with Bmab or AFL. The primary endpoint was median overall survival (OS). Secondary endpoints were median time to treatment failure (TTF), overall response rate (ORR) and incidence of adverse events.. Data from 26 patients in the Bmab group and 19 in the AFL group were analyzed. Median OS was slightly longer in the AFL group compared to the Bmab group, whereas median TTF was similar. ORR tended to be higher in the AFL group. The incidence of ≥grade 2 diarrhea and proteinuria was significantly higher in the AFL group than the Bmab group.. In patients given combination treatment with FOLFIRI for second-line treatment of mCRC, AFL can increase response rates compared to Bmab, which may contribute to longer survival.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retreatment; Treatment Outcome

The BEACON trial showed that combination therapy with encorafenib (BRAF inhibitor) and cetuximab (EGFR inhibitor) was associated with prolonged overall survival compared with standard chemotherapy in patients with metastatic BRAF variant colorectal cancer. However, the cost-effectiveness of using these agents in this clinical setting is unknown.. To create a cost-effectiveness model to compare doublet therapy (encorafenib plus cetuximab) with standard chemotherapy (cetuximab plus irinotecan or cetuximab plus folinic acid, fluorouracil, and irinotecan) in treating patients with metastatic BRAF variant colorectal cancer.. This economic evaluation constructed a Markov model to compare the lifetime cost and utility of doublet therapy and standard chemotherapy. Parametric survival modeling was used to extrapolate the effectiveness of each line of therapy from large clinical trials. One-way and probabilistic sensitivity analyses assessed the uncertainty in the model. Patients mirrored the cohorts in the BEACON trial: they had metastatic BRAF variant colorectal cancer and were followed up as they progressed through multiple lines of therapy, best supportive care, and death. Data collection and data analysis were performed from November 15, 2019, to July 14, 2020.. The main outcome was the incremental cost-effectiveness ratio, which was calculated using the cumulative cost and effectiveness in quality-adjusted life years (QALYs), of doublet therapy compared with standard chemotherapy.. The model patient cohort had a mean age of 61 years, and 53% of the patients were women, 66% had 1 previous line of therapy, and 8% had high microsatellite instability. Doublet therapy was associated with an improvement of 0.15 QALYs compared with standard chemotherapy. However, the incremental cost of doublet therapy was $78 233, leading to an incremental cost-effectiveness ratio of $523 374 per QALY gained. Concomitant decreases in the price of encorafenib and cetuximab are needed to achieve cost-effectiveness at a willingness-to-pay threshold of $150 000 per QALY gained.. This study found that doublet therapy for metastatic BRAF variant colorectal cancer was unlikely to be cost-effective under current pricing. Cost-effectiveness needs to be considered in clinical trial design, particularly when combining new therapies with non-cost-effective treatments that are coadministered without a fixed duration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Markov Chains; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins B-raf; Quality-Adjusted Life Years; Sulfonamides

FOLFOX (5-Fluorouracile and oxaliplatin) exhibits promising activity in advanced well-differentiated neuroendocrine tumors (NETs). This retrospective study aimed to analyze the outcome of metastatic enteropancreatic NETs patients treated with FOLFOX.. We retrospectively identified patients treated with FOLFOX for NETs of enteropancreatic or unknown origin among those referred to our Regional Multidisciplinary Tumor Board.. Among 48 patients, most often pancreatic NETs (n=33, 68.8%), the median Ki67 index was 10%. The median number cycle of FOLFOX was 6 and median follow-up was 34.8 months. Disease control rate (DCR) was 83.3%. Median PFS and OS were 12.6 and 29.4 months respectively. Median chemotherapy break was 14.1 months. No significant difference was observed between PFS and the following criteria: Ki67 index, primary tumor site, alkaline phosphatase levels, primary tumor surgery and. FOLFOX exhibits a high DCR and a short duration of treatment with a relative long chemotherapy break in patients with metastatic enteropancreatic NETs.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; France; Humans; Intestinal Neoplasms; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Organoplatinum Compounds; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome; Young Adult

To compare the treatment outcomes of gemcitabine with nab-paclitaxel (GnP) and modified FOLFIRINOX (mFFX; a combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin) for metastatic pancreatic cancer.. We retrospectively analyzed consecutive patients with metastatic or recurrent pancreatic cancer treated with GnP or mFFX as the first-line chemotherapy between March 2014 and December 2019 in our hospital. Treatment outcomes were compared using propensity score matching to adjust for age, sex, performance status, carcinoembryonic antigen levels, carbohydrate antigen 19-9 levels, and disease status (metastatic or recurrent).. Five hundred sixty-eight patients were included (GnP/mFFX, 456/112). After propensity score matching, 218 patients were extracted. The median age was around 61 years, and the proportion of performance status 0 was approximately 90%. The median overall survival values were 14.6 and 15.5 months (P = 0.45), and the median progression-free survival was 7.4 months (P = 0.53) for GnP and mFFX, respectively. The disease control rates were higher in the GnP group (82.6% vs 67.9%, P = 0.02). In nonhematologic adverse events, grade 3/4 anorexia and diarrhea occurred significantly more frequently in the mFFX group.. Gemcitabine with nab-paclitaxel had a higher disease control rate and lower rates of severe anorexia and diarrhea in our propensity-matched population.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Anemia; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Nausea; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Propensity Score; Retrospective Studies; Treatment Outcome

FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GnP) have been recommended as the first-line chemotherapy for metastatic pancreatic cancer (mPC). However, the evidence is lacking comparing not only two regimens, but also sequential treatment (FFX-GnP vs. GnP-FFX).. Data of 528 patients (FFX, n = 371; GnP, n = 157) with mPC were collected retrospectively. Propensity score matching was conducted to alleviate imbalance of the two groups. Overall survival (OS), progression free survival (PFS), and toxicity of patients were analyzed.. In the whole population, OS (12.5 months vs. 10.3 months, P = 0.05) and PFS (7.1 months vs. 5.8 months, P = 0.02) were longer in the FFX group before matching and after matching (OS: 11.8 months vs. 10.3 months, P = 0.02; PFS: 7.2 months vs. 5.8 months, P <  0.01). For sequential treatment, OS and PFS showed no significant difference. Interruptions of chemotherapy due to toxicities were more frequent (6.8 vs. 29.3%, P <  0.001) in the GnP group, and cessation of chemotherapy showed a significant association with mortality (z = - 1.94, P = 0.03).. FFX achieved a longer overall survival than GnP in mPC, but not in the comparison for sequential treatment. More frequent adverse events followed by treatment interruptions during GnP might lead to a poor survival outcome. Therefore, FFX would be a better first-line treatment option than GnP for mPC.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Propensity Score

The efficacy of folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab (F-RAM) or aflibercept (F-AFL) as a second-line treatment in metastatic colorectal cancer (mCRC) is established. In this study, the risks and benefits of F-RAM/AFL as a third-line treatment after first- and second-line bevacizumab for mCRC were evaluated.. Overall survival (OS) and adverse events (AEs) were compared between groups treated with F-RAM/AFL (n=17) and trifluridine/tipiracil combination tablet (TAS-102) (n=26).. Median OS was longer in the third-line F-RAM/AFL group (379 days; 95%CI=157-458 days) than in the TAS-102 group (183 days; 95%CI=80-204 days) (log-rank test, p=0.015). Discontinuation due to AEs was only observed in the F-RAM/AFL group (3 cases).. As a third-line treatment for mCRC, F-RAM/AFL should be prioritized over TAS-102 in terms of efficacy; however, the risk of AEs should be considered.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Ramucirumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

Recent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF-mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study.. Clinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy.. Of 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P < 0.001).. Gene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis

Since 2016, bevacizumab has been widely used to treat metastatic colorectal cancer (mCRC) in Indonesia. Nevertheless, the high cost of bevacizumab has raised the question of whether the therapy is considered cost-effective and should be included in the national health insurance system. This study aimed to assess the cost-effectiveness of bevacizumab plus chemotherapy versus chemotherapy alone for the treatment of mCRC patients.. A Markov model was applied using the perspective of the Indonesian healthcare system to assess cost-effectiveness. The health outcomes were expressed in terms of quality-adjusted life years (QALY) using the validated EuroQoL-5D-5L instrument. Data for medical costs were collected from hospital billings in four hospitals located in three different cities in Indonesia. Meanwhile, data for utility were obtained from interviewing 90 patients who came to the hospital. We compared those mCRC patients who received chemotherapy alone either with FOLFOX or FOLFIRI, versus patients who received the addition of bevacizumab.. With the perspective of societal, the incremental cost-effectiveness ratio (ICER) of adding bevacizumab was USD 49,312 per QALY gained using secondary data and USD 28,446 per QALY using real world data.. Using either a healthcare or societal perspective, the addition of bevacizumab for mCRC treatment was considered not cost-effective.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Cost-Benefit Analysis; Fluorouracil; Humans; Indonesia; Leucovorin; Markov Chains; Neoplasm Metastasis; Organoplatinum Compounds; Quality-Adjusted Life Years

Optimal sequence of therapy for patients with metastatic pancreatic ductal adenocarcinoma is unknown. Combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel + gemcitabine (nab-p/gem) are standard first-line (1L) therapies. They have never been prospectively compared. We retrospectively compared overall survival (OS) of patients treated with 1L nab-p/gem and second-line (2L) FOLFIRINOX with those treated with the reverse sequence.. Patients with metastatic pancreatic ductal adenocarcinoma treated with 1L FOLFIRINOX and 2L nab-p/gem or vice versa were identified using an electronic health record-derived real-world database. Using an intent-to-treat analysis, we compared OS from initiation of 1L therapy. A Cox model, stratified by deciles of propensity score, estimated the effect of treatment sequence on OS.. The study included 3027 patients. The median OS for 1L FOLFIRINOX versus nab-p/gem was 8.6 versus 6.1 months (hazard ratio, 0.77; 95% confidence interval, 0.70-0.84). The median OS for 1L FOLFIRINOX and 2L nab-p/gem versus 1L nab-p/gem and 2L FOLFIRINOX was 11.9 versus 11.5 months (hazard ratio, 0.97; 95% confidence interval, 0.79-1.18).. In this analysis of real-world data, 1L FOLFIRINOX was associated with increased OS in propensity analysis. For patients who received both FOLFIRINOX and nab-p/gem, median OS was similar regardless of sequence.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Outcome Assessment, Health Care; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Proportional Hazards Models; Retrospective Studies

The use of FOLFIRINOX (a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) is one of the therapeutic standards in pancreatic adenocarcinoma. We analyzed progression-free survival (PFS) and overall survival (OS) and their predictive factors in patients treated with FOLFIRINOX as first-line therapy in metastatic pancreatic cancer.. This multicenter retrospective analysis included patients treated with FOLFIRINOX between 2011 and 2015. The Kaplan-Meier method was used to estimate OS and PFS. The statistical comparison for survival was performed by the log-rank test. Predictive factors were estimated in multivariate analysis with the use of a Cox model.. One hundred and thirty-six patients were included (74 men, 62 women; median age, 62 years [range, 29-74 years]). The median PFS was 5.97 months (95% confidence interval, 4.4-6.63 months). The median OS was 8.93 months (95% confidence interval, 7.4-10.07 months). Prognostic factors in multivariate analysis were the use of granulocyte colony-stimulating factor, which appeared to be a good prognostic factor. Dose intensity of oxaliplatin (≥74.48%) and dose intensity of bolus of fluorouracil (>6.9%) appeared as pejorative factors.. In patients with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX in first line, dose modifications at the onset of adverse effects and early use of granulocyte-colony stimulating factor seem to be associated with a better survival.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multivariate Analysis; Nausea; Neoplasm Metastasis; Neutropenia; Outcome Assessment, Health Care; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Vomiting

Despite introduction of new chemotherapeutic agents, outcomes of patients with metastatic pancreatic cancer are still poor. Metabolically supported chemotherapy (MSCT) is a novel approach targeting dysregulated energy mechanism of the tumor cell.. This study aimed to examine the efficacy of metabolically supported administration of chemotherapy combined with ketogenic diet, hyperthermia, and hyperbaric oxygen therapy (HBOT) in patients with metastatic pancreatic cancer.. This retrospective observational study included 25 patients with metastatic pancreatic ductal carcinoma (stage IV) who received MSCT (either gemcitabine-based or FOLFIRINOX regimen administered concomitantly with induced hypoglycemia) plus ketogenic diet, hyperthermia, and HBOT combination. Survival outcomes were evaluated.. During the mean follow-up duration of 25.4 ± 19.3 months, median overall survival and median progression-free survival were 15.8 months (95% CI, 10.5-21.1) and 12.9 months (95% CI, 11.2-14.6), respectively. Age and gender did not have any effect on overall survival (p > 0.05 for all).. MSCT administered together with ketogenic diet, hyperthermia, and HBOT appears to be a viable option with the potential to improve survival outcomes in patients diagnosed with metastatic pancreatic cancer. Further research, particularly with larger comparative clinical trials, is warranted.. Hintergrund: Trotz der Einführung neuer Chemotherapeutika sind die Verlaufsaussichten von Patienten mit metastasierendem Pankreaskarzinom weiterhin ungüns­tig. Die metabolisch unterstützte Chemotherapie (metabolically supported chemotherapy, MSCT) ist ein neuartiger Ansatz, der auf den entgleisten Energiehaushalt der Tumorzelle abzielt. Ziele: Ziel dieser Studie war die Untersuchung der Wirksamkeit einer MSCT in Kombination mit ketogener Ernährung, Hyperthermie und hyperbarer Sauerstofftherapie (HBOT) bei Patienten mit metastasierendem Pankreaskarzinom. Methoden: In dieser retrospek­tiven Beobachtungsstudie betrachteten wir 25 Patienten mit metastasierendem duktalem Pankreaskarzinom (Stadium IV), die mit einer Kombination aus MSCT (Gemcitabin-haltiges oder FOLFIRINOX-Schema, verabreicht unter induzierter Hypoglykämie) mit ketogener Ernährung, Hyperthermie und HBOT behandelt wurden. Verschiedene Überlebenskennzahlen wurden ausge­wertet. Ergebnisse: Während eines mittleren Nachbeobachtungszeitraums von 25,4 ± 19,3 Monaten betrug das mediane Gesamtüberleben 15,8 Monate (95%-KI: 10,5–21,1) und das mediane progressionsfreie Überleben 12,9 Monate (95%-KI: 11,2–14,6). Alter und Geschlecht hatten keinen Einfluss auf das Gesamtüberleben (p > 0,05 für alle). Schlussfolgerungen: MSCT in Kombination mit ketogener Ernährung, Hyperthermie und HBOT scheint bei Patienten mit metastasierendem Pankreaskarzinom eine praktikable Behandlungsoption mit Potenzial zur Verbesserung von Überlebens-Outcomes zu sein. Weitere Forschung hierzu ist gerechtfertigt, insbesondere in Form größerer vergleichender klinischer Studien.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Deoxycytidine; Diet, Ketogenic; Female; Fluorouracil; Gemcitabine; Humans; Hyperbaric Oxygenation; Hyperthermia, Induced; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Survivors

Induction of memory T cell response is inefficient in colorectal cancer (CRC) liver metastasis following existing therapies due to abundant stroma and immunosuppressive environment within the metastatic liver, which leads to fast disease progression, high recurrence rate, and short survival. Two fundamental steps are involved to elicit extensive memory T cell response: stimulation of naive T cells with robust and persistent antigen signals; and maintenance of differentiated memory T cells with survival factors. Here, we demonstrate a rational design of triple combination regimen, including relaxin (RLN), FOLFOX (combination of 5-fluorouracil, leucovorin, and oxaliplatin), and IL-12, successfully stimulates central memory T cells and achieves long-term survival in an aggressive experimental CRC liver metastasis model. Sequential administration of FOLFOX and IL-12 gene therapy following stromal deactivation by RLN gene therapy completely cured established CRC liver metastases in ~50% of mice and provided long-lasting protection against tumor recurrence. The study here may highlight the potential of evoking memory response as a curative therapy for the treatment of CRC liver metastasis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Interleukin-12; Leucovorin; Liver Neoplasms; Mice; Neoplasm Metastasis; Organoplatinum Compounds; Relaxin; Treatment Outcome

Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients.. In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19-9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed.. As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in a APC/TP53/KRAS triple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.

Topics: Adenomatous Polyposis Coli Protein; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cell-Free Nucleic Acids; Circulating Tumor DNA; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liquid Biopsy; Male; Middle Aged; Mutation; Neoplasm Metastasis; Proto-Oncogene Proteins p21(ras); Remission Induction; Tumor Suppressor Protein p53

The NCT00339183 trial demonstrated that adding panitumumab to fluorouracil, leucovorin and irinotecan (FOLFIRI) as a second-line therapy of wild-type RAS metastatic colorectal cancer (mCRC) increases the median progression-free survival (PFS). Nevertheless, panitumumab is not yet approved in China, and the costs and outcomes of the therapy are still unclear. We estimated the cost-effectiveness of this intervention from the perspective of Chinese health care systems by constructing two pricing scenarios for panitumumab. Scenario 1: Pricing is based on the price of a similar product (cetuximab) in China. Scenario 2: We estimated the value-based price.. A partitioned survival model was created based on the results of the NCT00339183 trial, which evaluated panitumumab plus FOLFIRI versus FOLFIRI. The model simulated the disease progression. We calculated medical costs from the perspectives of the Chinese health care systems. The primary outcome measures were costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs).. In scenario 1, compared with FOLFIRI alone, FOLFIRI with panitumumab arm had an ICER of ¥1,539,988/QALY. The most influential factors were the mean overall survival (OS), utility before progression and cost of panitumumab. The probability of panitumumab plus FOLFIRI being cost-effective in China was 0% when the willingness-to-pay (WTP) threshold was ¥193,932/QALY. In scenario 2, when the cost of panitumumab was assumed to be ¥4032.61 or ¥5218.96 per cycle, the ICERs approximated the WTP thresholds of ¥193,932/QALY or ¥420,633/QALY, respectively. In this value-based pricing scenario, panitumumab plus FOLFIRI is estimated to be cost-effective.. We construct two pricing scenarios in China. In scenario 1, panitumumab plus FOLFIRI as a second-line therapy of mCRC provided an incremental benefit, but simultaneously increased costs (at the current price) even further. In scenario 2, when the value-based price was adopted, panitumumab plus FOLFIRI was estimated to be cost-effective. Our study establishes a pricing framework for new anticancer drugs to reflect the economics of drugs.. NCT00339183.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; China; Colorectal Neoplasms; Cost-Benefit Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Panitumumab; Quality-Adjusted Life Years

The purposes of this study were to assess the levels of symptom distress, body image, and epidermal growth factor receptor inhibitors (EGFRI)-associated health-related quality of life (QoL); identify the factors related to EGFRI-associated health-related QoL; and examine the differences in EGFRI-associated health-related QoL by grade of skin toxicity in mCRC patients receiving target therapy.. This cross-sectional study examined mCRC patients who received cetuximab-based target therapy from the oncology and CRC inpatient and outpatient departments of a medical center in northern Taiwan. Structured questionnaires were used to measure patients' symptom distress, body image, and EGFRI-associated health-related QoL.. Of the 111 mCRC patients studied, 79.2% reported acneiform eruption and 52.2% reported paronychia. The most common symptoms were dry skin and itching. Poor EGFRI-associated health-related QoL was associated with more symptom distress, more negative body image, a higher cumulative dose of target therapy, and being married; these factors explained 66.6% of the variance in EGFRI-associated health-related QoL.. Patient-specific skin care and emotional support are needed to relieve distressful dermatological symptoms and emotional distress during and post-treatment for mCRC.

Topics: Acneiform Eruptions; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Body Image; Camptothecin; Cetuximab; Colorectal Neoplasms; Cross-Sectional Studies; ErbB Receptors; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Paronychia; Protein Kinase Inhibitors; Pruritus; Quality of Life; Skin Diseases; Surveys and Questionnaires

Liposomal irinotecan (nal-IRI) is a topoisomerase inhibitor proven to improve survival in metastatic pancreatic cancer (mPC). This study describes real-world characteristics of patients treated with nal-IRI for mPC.. Patients 18 years or older diagnosed with stage IV mPC and treated with nal-IRI were selected retrospectively from a deidentified electronic health record database of more than 2 million US cancer patients. Demographics, clinical and dosing characteristics, and treatment outcomes were collected.. Of 257 total patients, 145 (57%) received nal-IRI as first- or second-line therapy. Median nal-IRI treatment duration was 51 days, longer when nal-IRI was used as first/second versus as third-line therapy or later (62 vs 44.5 days). Seventy patients (27.2%) experienced dose modification. Median time to treatment discontinuation was 2.3 versus 1.6 months for first-/second- versus third-line therapy or later, respectively. Median overall survival from nal-IRI initiation was 5.6 versus 4.1 months for first-/second- versus third-line therapy or later, respectively. Prior irinotecan treatment, baseline serum albumin less than 40 g/L, and baseline neutrophil-to-lymphocyte ratio greater than 5 were associated with reduced overall survival.. This is the first large US study of real-world US mPC patients treated with nal-IRI. These results, comparable to the NAPOLI-1 trial, can help inform future studies and the efficacy of nal-IRI in mPC therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neutropenia; Outcome Assessment, Health Care; Pancreatic Neoplasms; Retrospective Studies; United States

The standard first- and second- line chemotherapy backbone regimens for metastatic colorectal cancer (mCRC) are 5-fluorouracil (5-FU)/capecitabine-based with addition of irinotecan or oxaliplatin. Until recently, evidence for optimal sequencing post second-line was sparse. Trifluridine/tipiracil (indicated for mCRC and gastric cancer after standard chemotherapies) was made available to UK patients via a named patient programme (NPP) before receiving marketing authorisation in Europe in 2016, allowing characterisation of UK treatment pathways, and evaluation of trifluridine/tipiracil in a UK non-trial population.. Data collected routinely for the NPP were analysed to describe the patient demographics, clinical characteristics and treatment pathways. Patients eligible for the programme were adults (≥18 years) with histologically or cytologically confirmed mCRC who had previously received chemotherapy treatment(s).. Of the 250 eligible patients enrolled in the NPP, 194 patients received ≥1 dose of trifluridine/tipiracil and 56 patients did not receive trifluridine/tipiracil. The following results are reported first for patients who received trifluridine/tipiracil and second for those who did not receive trifluridine/tipiracil: median (IQR) age was 63.0 (54.0-69.0) and 62.0 (54.8-69.0) years; Eastern Cooperative Oncology Group performance status score was 0 for 28 and 14%, 1 for 65 and 70%, 2 for 7 and 16%. In terms of previous systemic treatments 47 and 43% had 2 prior lines of therapy. FOLFOX-, FOLFIRI- and CAPOX-based therapies were the most common first-line regimens in patients receiving trifluridine/tipiracil (37, 35 and 21%, respectively), and in patients not receiving trifluridine/tipiracil (41, 30 and 20%, respectively). Second-line treatment regimens in patients receiving and not receiving trifluridine/tipiracil were most commonly FOLFIRI-based (48 and 41%, respectively) and FOLFOX-based (19 and 21%, respectively). Patients received a median of 2 cycles of trifluridine/tipiracil with a median treatment duration of 1.8 (95% CI: 1.8-2.4) months. In patients who discontinued treatment due to disease progression, the median progression-free duration was 2.8 (95% CI: 2.4-2.9) months.. The results highlight the number of treatment pathways used to treat mCRC in routine UK clinical practice prior to the marketing authorisation and National Institute for Health and Care Excellence approval of trifluridine/tipiracil and highlight the lack of clinical guidelines for mCRC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Pyrrolidines; Thymine; Treatment Outcome; Trifluridine; United Kingdom; Uracil

The authors sought to forecast survival and enhance treatment decisions for patients with liver metastatic colorectal cancer by using on-treatment radiomics signature to predict tumor sensitiveness to irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) alone (F) or in combination with cetuximab (FC).. We retrospectively analyzed 667 metastatic colorectal cancer patients treated with F or FC. Computed tomography quality was classified as high (HQ) or standard (SD). Four datasets were created using the nomenclature (treatment) - (quality). Patients were randomly assigned (2:1) to training or validation sets: FCHQ: 78:38, FCSD: 124:62, FHQ: 78:51, FSD: 158:78. Four tumor-imaging biomarkers measured quantitative radiomics changes between standard of care computed tomography scans at baseline and 8 weeks. Using machine learning, the performance of the signature to classify tumors as treatment sensitive or treatment insensitive was trained and validated using receiver operating characteristic (ROC) curves. Hazard ratio and Cox regression models evaluated association with overall survival (OS).. The signature (area under the ROC curve [95% confidence interval (CI)]) used temporal decrease in tumor spatial heterogeneity plus boundary infiltration to successfully predict sensitivity to antiepidermal growth factor receptor therapy (FCHQ: 0.80 [95% CI = 0.69 to 0.94], FCSD: 0.72 [95% CI = 0.59 to 0.83]) but failed with chemotherapy (FHQ: 0.59 [95% CI = 0.44 to 0.72], FSD: 0.55 [95% CI = 0.43 to 0.66]). In cetuximab-containing sets, radiomics signature outperformed existing biomarkers (KRAS-mutational status, and tumor shrinkage by RECIST 1.1) for detection of treatment sensitivity and was strongly associated with OS (two-sided P < .005).. Radiomics response signature can serve as an intermediate surrogate marker of OS. The signature outperformed known biomarkers in providing an early prediction of treatment sensitivity and could be used to guide cetuximab treatment continuation decisions.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Biomarkers, Tumor; Cetuximab; Cohort Studies; Colorectal Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Image Processing, Computer-Assisted; Irinotecan; Leucovorin; Liver Neoplasms; Male; Molecular Targeted Therapy; Neoplasm Metastasis; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Signal Transduction; Tomography, X-Ray Computed; Transcriptome

Colorectal cancer (CRC) is the third most prevalent cancer in China but few large-scale studies were conducted to understand CRC patients. The current study is aimed to gain a real-world perspectives of CRC patients in China.. Using electronic medical records of sampled patients between 2011 and 2016 from 12 hospitals in China, a retrospective cohort study was conducted to describe demographics and disease prognosis of CRC patients, and examine treatment sequences among metastatic CRC (mCRC) patients. Descriptive, comparative and survival analyses were conducted.. Among mCRC patients (3878/8136, 48%), the fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and other oxaliplatin-based regimens were the most widely-used first-line treatment (42%). Fluorouracil, leucovorin, irinotecan (FOLFIRI) and other irinotecan-based regimens dominated the second-line (40%). There was no a dominated regimen for the third-line. The proportion of patients receiving chemotherapy with targeted biologics increased from less than 20% for the first- and second- lines to 34% for the third-line (p < 0.001). The most common sequence from first- to second-line was from FOLFOX and other oxaliplatin-based regimens to FOLFIRI and other irinotecan-based regimens (286/1200, 24%).. Our findings reflected a lack of consensus on the choice of third-line therapy and limited available options in China. It is evident o continue promoting early CRC diagnosis and to increase the accessibility of treatment options for mCRC patients. As the only nationwide large-scale study among CRC and mCRC patients before more biologics became available in China, our results can also be used as the baseline to assess treatment pattern changes before and after more third-line treatment were approved and covered into the National Health Insurance Plan in China between 2017 and 2018.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; China; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Medical Records; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Staging; Oxaliplatin; Retrospective Studies; Survival Rate; Treatment Outcome; Young Adult

There are obviously ethnic differences between the UGT1A1 gene polymorphisms. Due to the difference of genetic background and environment, the treatment with colorectal cancer patients of Guangxi Zhuang should not completely follow the Euramerican or Chinese han patients. The study aimed to explore the correlation of UGT1A1 gene polymorphism of Guangxi Zhuang metastatic colorectal cancer (mCRC) with irinotecan -based chemotherapy, in order to develop an individualized irinotecan regimen for mCRC patients of Guangxi Zhuang.. From June 2013 and June 2015, a total of 406 patients of Guangxi who were histologically diagnosed as metastatic colorectal cancer with 102 patients of this cohort with three generations of Zhuang, and 86 patients that conformed to inclusion and exclusion criteria were competitively enrolled. The distribution of UGT1A1 gene polymorphism was analyzed-retrospectively in all patients. Pyrosequencing method was used to detect the UGT1A1*28 and*6 gene polymorphism in the 86 Guangxi Zhuang mCRC patients. After first-line chemotherapy with FOLFIRI regimen, the relationship between gene polymorphism of UGT1A1 and adverse reactions, and efficacy of Irinotecan were analyzed with χ2 test and Kaplan-Meier method.. UGT1A1*28 wild-type (TA6/6), heterozygous mutant (TA6/7) and homozygous mutant (TA7/7) accounted for 69.8, 30.2 and 0%, respectively. UGT1A1*6 wild type (G/G), heterozygous mutation type (G/A) and homozygous mutant (A/A) accounted for 76.7%, 20.9 and 2.3%, respectively. UGT1A1*28 TA6/7 type could increase the risk of grade 3~4 diarrhea (p = 0.027), which did not increase the risk of grade 3~4 neutropenia (p = 0.092). UGT1A1*6G/A and A/A type could increase the risk of grade 3~4 diarrhea and neutropenia (p = 0.001; p = 0.017). After chemotherapy with FOLFIRI, there was no significant difference in response rate (RR) (p = 0.729; p = 0.745) or in median progression-free survival (mPFS) between the wild-type, mutant treatment of UGT1A1*28 and UGT1A1*6 (7.0 m vs 7.4 m, p = 0.427; 6.9 m vs 7.0 m p = 0.408).. The distribution of UGT1A1*28 and UGT1A1*6 gene polymorphism in Guangxi Zhuang patients were differed from the existing reported of European people and Chinese Han population. The UGT1A1 gene polymorphism with irinotecan chemotherapy-associated diarrhea and neutropenia were closely related. There was no significant association between UGT1A1 gene polymorphism and therapeutic efficacy of irinotecan.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; China; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Polymorphism, Genetic; Precision Medicine; Progression-Free Survival; Retrospective Studies; Treatment Outcome

Cetuximab plus FOLFIRI (leucovorin, fluorouracil, and irinotecan) is the preferred first-line therapy for RAS and BRAF wild-type (RBWT) metastatic colorectal cancer (mCRC). To counter chemotherapy-induced side effects, use of maintenance therapy is suggested. Therefore, we evaluated the efficacy and safety of cetuximab maintenance therapy in patients after effective completion of first-line induction therapy.. This prospective study enrolled untreated patients with mCRC RBWT who received first-line cetuximab plus FOLFIRI therapy. Following this, patients with treatment response either entered observation (stop treatment) or maintenance treatment 1 (cetuximab plus irinotecan) groups. After 6-12 cycles of maintenance treatment 1, patients entered maintenance treatment 2 (cetuximab only). If a patient progressed on maintenance 2, cetuximab plus FOLFIRI was reintroduced. The primary end point was failure-free survival (FFS), whereas the secondary end points included disease control rate (DCR), objective remission rate (ORR), and progression-free survival (PFS). Safety events were also evaluated.. Among 79 enrolled patients, 72 completed first-line treatment effectively (DCR 91.1%, ORR 63.9%) and 44 entered maintenance 1 [median PFS 1 (mPFS, maintenance 1) 6.1 months, 95% confidence interval (CI) 6.0-6.2; DCR 56.8%; ORR 22.7%]. Of them, 21 entered maintenance treatment 2 (mPFS2 8.7 months, 95% CI 3.3-14.1; DCR 28.6%; ORR 4.8%). Median FFS (mFFS) was significantly longer in the maintenance 1 group compared with the observation group [12.7 vs. 3.0 months; hazard ratio (HR) 0.202, 95% CI 0.111-0.369; P < 0.001]. Overall, mFFS was 19.0 and 9.3 months in maintenance and observation groups, respectively (HR 0.211, 95% CI 0.117-0.380; P < 0.001). Rash acneiform, mucositis, and asthenia were commonly observed adverse events during maintenance treatment.. Maintenance treatment with cetuximab after first-line therapy significantly improved FFS, with an acceptable safety profile in untreated patients with mCRC RBWT.. Retrospectively registered, 2019/10/02, Chinese Clinical Trial Registry, ChiCTR number 1900026360.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Progression-Free Survival; Prospective Studies; Proto-Oncogene Proteins B-raf; Young Adult

Topics: Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colon; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds

A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment.. Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumours.. A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.207-0.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.113-0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001).. PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.. Project funding was provided by INCa (Grants number 2018-078 and 2018-079, BACAP BCB INCa_6294), Canceropole PACA, DGOS (labellisation SIRIC), Amidex Foundation, Fondation de France, INSERM and Ligue Contre le Cancer.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Line, Tumor; Clinical Trials as Topic; Disease-Free Survival; Drug Resistance, Neoplasm; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Irinotecan; Leucovorin; Male; Mice; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Oxaliplatin; Pancreatic Neoplasms; Precision Medicine; Prognosis; Transcriptome; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Metastasis; Neoplasm Proteins; Organoplatinum Compounds

Triplet chemotherapy (FOLFOXIRI) + bevacizumab regimen is indicated as first-line treatment of BRAF-mutated metastatic colorectal cancer (mCRC). Nevertheless, its proven therapeutic efficacy in clinical trials was solely based on partial morphologic responses assessed by CT. To date, only 1 case of complete response assessed by FDG PET/CT was reported in literature in BRAF-mutated mCRC, but treated with doublet chemotherapy (FOLFIRI) + cetuximab regimen. We report a complete metabolic response assessed by FDG PET/CT, maintained over time (13 months) in a 60-year-old woman with BRAF-mutated mCRC treated by FOLFOXIRI-bevacizumab. This also confirms that FDG PET/CT is emerging as a useful approach for therapeutic assessment of targeted drugs in mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorodeoxyglucose F18; Fluorouracil; Humans; Leucovorin; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Positron Emission Tomography Computed Tomography; Proto-Oncogene Proteins B-raf; Treatment Outcome

Enzymatic variants involved in fluoropyrimidine metabolism have been associated with adverse events (AEs). We assessed the association between C677T (rs1801133) and A1298 (rs1801131) methylenetetrahydrofolate reductase (MTHFR) polymorphisms and AEs in patients with first-line fluoropyrimidine-based chemotherapy.. Fifty patients with metastatic colorectal cancer were prospectively followed-up during the first 4 cycles of fluoropyrimidine-based treatment to assess AEs. Germline DNA was analyzed to determine the C677T and A1298C MTHFR polymorphisms. The associations between MTHFR polymorphisms and toxicity were examined.. Individuals carrying at least one mutant allele of the MTHFR C677T polymorphism had increased risk to experience anemia (OR=1.69, 95% CI=1.13-2.53, p=0.005), neutropenia (OR=2.27, 95% CI=1.47-3.42, p<0.001) thrombocytopenia (OR=1.91, 95% CI=1.30-2.70, p<0.001), neuropathy (OR=1.77, 95% CI=1.16-2.70, p=0.02), diarrhea (OR=1.69, 95% CI=1.13-2.53, p=0.005), and hand-foot syndrome (OR=1.56, 95% CI=1.08-2.27, p=0.013), compared to patients carrying the wild type alleles. The presence of the mutant allele C of the MTHFR A1298C polymorphism was associated with increased risk of anemia (OR=2.75, 95% CI=1.01-7.48, p=0.02) and thrombocytopenia (OR=3.14, 95% CI=1.01-9.78, p=0.03); however, the prevalence of this allele in the sample was quite low (20%).. MTHFR C677T and A1298C polymorphisms predicted toxicity in a subset of Mestizo patients with colorectal adenocarcinoma.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Costa Rica; Ethnicity; Female; Fluorouracil; Humans; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Prospective Studies

Objectives: Pancreatic cancer (PC) is a costly disease with a limited life-expectancy as it generally presents as an advanced, metastatic disease. Though current literature suggests cost varies by first line treatment, there is limited real-world knowledge about the economic burden of pancreatic cancer. This study describes the economic burden of pancreatic cancer patients overall and by observed first line treatments.. The IBM MarketScan databases were used to identify adult metastatic PC patients from January 1, 2010 through 3/31/2017. Those without other primary cancers, pregnancy, or prior PC treatment, and with 6 months of continuous enrollment prior to PC were included. Treatment patterns and healthcare utilization and expenditures were measured during the variable-length follow-up period. Continuous measures were presented as per patient per month (PPPM).. A total of 6,360 patients met all inclusion criteria. Almost half (46.8%) of patients were untreated. Gemcitabine alone (15.6%) and FOLFIRINOX (11.4%) were the most commonly observed first line regimens. Treated patients incurred $17,513 PPPM (Gemcitabine alone) to $27,889 PPPM (FOLFIRINOX) during follow-up. Untreated patients incurred the highest unadjusted ($30,777 PPPM) and adjusted ($20,392 PPPM) cost.. Metastatic PC patients incur a high economic burden driven by high utilization of healthcare resources, which varies by first line treatment. Also, the high proportion of untreated patients is alarming as these patients may be the most expensive of all patients. There is an unmet need in these patients for effective treatments that also reduce their economic burden.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cost of Illness; Costs and Cost Analysis; Databases, Factual; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Health Care Costs; Health Resources; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Needs Assessment; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

Chemotherapy resistance remains a challenge in the clinical management of metastatic colorectal cancer (mCRC). Here, early changes in cell-free circulating tumour DNA (ctDNA) levels were explored as a marker of therapeutic efficacy. Twenty-four mCRC patients were enrolled and treated with FOLFIRI based first-line therapy. Blood samples collected pre-treatment, at day 7, 14, 21, 60 and at progression were analysed for cell-free DNA (cfDNA) and ctDNA levels using digital droplet PCR. A subset of samples were additionally analysed by targeted sequencing. Patients with high pre-treatment ctDNA or cfDNA levels (≥75

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Cell-Free Nucleic Acids; Circulating Tumor DNA; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Progression-Free Survival; Treatment Outcome

Conversion chemotherapy is often used for borderline or unresectable (B/U) liver metastases from colorectal cancer (CRC) with the aim of achieving resectability. Although intensive and costly regimens are often used, the best regimen in this scenario remains unclear. We aimed to evaluate the outcomes of patients with B/U liver metastases from CRC treated with conversion chemotherapy with the modified fluorouracil, leucovorin, and oxaliplatin (mFLOX) regimen followed by metastasectomy.. We performed a single-center retrospective analysis of patients with B/U liver metastases from CRC treated with chemotherapy with the mFLOX regimen followed by surgery. B/U disease was defined as at least one of the following: more than four lesions, involvement of hepatic artery or portal vein, or involvement of biliary structure.. Fifty-four consecutive patients who met our criteria for B/U liver metastases were evaluated. Thirty-five patients (64%) had more than four liver lesions, 16 (29%) had key vascular structure involvement, and 16 (29%) had biliary involvement. After chemotherapy, all patients had surgery and 42 (77%) had R0 resection. After a median follow-up of 37.2 months, median progression-free survival (PFS) was 16.9 months and median overall survival (OS) was 68.3 months. R1-R2 resections were associated with worse PFS and OS compared with R0 resection (PFS: hazard ratio, 2.65;. Treatment of B/U liver metastases from CRC with conversion chemotherapy using mFLOX regimen followed by surgical resection was associated with a high R0 resection rate and favorable survival outcomes. On the basis of our results, we consider mFLOX a low-cost option for conversion chemotherapy among other options that have been proposed.

Topics: Adult; Aged; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Retrospective Studies; Young Adult

This study investigated the potential of single nucleotide polymorphisms as predictors of survival in two cohorts comprising 417 metastatic colorectal cancer (mCRC) patients treated with the FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) regimen. The rs4806668G > T of the ribosomal protein gene RPL28 was associated with shorter progression-free survival and overall survival by 5 and 9 months (P = 0.002), with hazard ratios of 3.36 (P < 0.001) and 3.07 (P = 0.002), respectively. The rs4806668T allele was associated with an increased RPL28 expression in transverse normal colon tissues (n = 246, P = 0.007). RPL28 expression was higher in colorectal tumors compared to paired normal tissues by up to 124% (P < 0.001) in three independent datasets. Metastatic cases with highest RPL28 tumor expression had a reduced survival in two datasets (n = 88, P = 0.009 and n = 56, P = 0.009). High RPL28 was further associated with changes in immunoglobulin and extracellular matrix pathways. Repression of RPL28 reduced proliferation by 1.4-fold to 5.6-fold (P < 0.05) in colon cancer HCT116 and HT-29 cells. Our findings suggest that the ribosomal RPL28 protein may influence mCRC outcome.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Cohort Studies; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Germ Cells; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Polymorphism, Single Nucleotide; Prognosis; Ribosomal Proteins; Survival Rate; Tumor Cells, Cultured

Data about the use and effectiveness of targeted therapy in metastatic small bowel adenocarcinoma (SBA) are scarce.. The aim of this population-based study was to obtain insights into the use and effectiveness of targeted therapy in patients with synchronous metastases of SBA.. Data were retrieved from the Netherlands Cancer Registry. Patients treated with palliative chemotherapy and/or targeted therapy for synchronous metastatic SBA between 2007 and 2016 were included (n = 187). Differences in treatment and the subsequent effects on overall survival (OS) were evaluated.. In first-line treatment, 25 patients (13%) received additional targeted therapy, exclusively bevacizumab, and mostly in combination with CAPOX/FOLFOX (n = 24). A primary ileal tumour was predictive for receiving bevacizumab in first-line treatment (odds ratio 3.2, 95% confidence interval (CI) 1.06-9.93). Median OS for patients in whom bevacizumab was added to first-line chemotherapy was 9.3 months, compared to 9.1 months with chemotherapy only (p = 0.85). Median OS for patients receiving first-line treatment only was 8.5 months with and 6.4 months without the addition of bevacizumab, respectively (p = 0.54). In multivariable survival analyses, the addition of bevacizumab was no prognostic factor (hazard ratio 1.01, 95% CI 0.65-1.59).. Bevacizumab was the only prescribed targeted therapy in first-line treatment. Considering the limited number of patients receiving first-line bevacizumab and the unknown reasons to prescribe additional targeted therapy, the corresponding survival rates of patients treated with and without additional bevacizumab in first-line treatment might suggest a limited clinical effect of bevacizumab in addition to first-line palliative chemotherapy on OS. Future research should focus on identifying the subgroup of patients who might benefit from anti-VEGF therapy in metastatic SBA.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Female; Fluorouracil; Humans; Intestinal Neoplasms; Intestine, Small; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Netherlands; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Prognosis; Quinazolines; Registries; Retrospective Studies; Survival Rate

Studies of patients treated with bevacizumab and other vascular epithelial growth factor (VEGF) inhibitors have reported that hypertension adverse events (AEs) are associated with improved overall survival (OS) or progression-free survival (PFS).. Our objective was to evaluate the association between early AEs and survival outcomes for patients treated with ramucirumab, an antibody targeting the VEGF receptor-2 (VEGFR-2), plus FOLFIRI for metastatic colorectal cancer (mCRC).. Data from 529 patients treated with ramucirumab plus FOLFIRI for mCRC in the RAISE clinical trial (NCT01183780) were evaluated to see whether early (first 6 weeks of therapy) AEs predicted subsequent OS and PFS. A Cox proportional hazard approach was used to evaluate associations between early AEs and survival outcomes. A secondary analysis between FOLFIRI and placebo was conducted as a sensitivity analysis.. Of 529 patients treated with ramucirumab plus FOLFIRI, 479 were alive and progression free at 6 weeks after commencing therapy. No significant association was identified between hypertension occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and OS (grade 1-2, hazard ratio [HR] 0.90 [95% confidence interval (CI) 0.66-1.24]; grade 3+, HR 1.02 [95% CI 0.67-1.55]; P = 0.803) or PFS (grade 1-2, HR 0.98 [95% CI 0.74-1.28]; grade 3+, HR 0.93 [95% CI 0.64-1.37]; P = 0.93). However, there was a significant association between diarrhea occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and worse OS (grade 1-2, HR 0.96 [95% CI 0.76-1.20]; grade 3+, HR 2.72 [95% CI 1.67-4.44]; P = 0.001) and PFS (grade 1-2, HR 1.01 [95% CI 0.83-1.23]; grade 3+, HR 2.22 [95% CI 1.43-3.45]; P = 0.005). No other AEs were significantly associated with OS or PFS.. Ramucirumab-induced hypertension was not associated with improved OS and PFS in patients with mCRC treated with ramucirumab and FOLFIRI, but severe diarrhea was associated with poorer OS and PFS.. No. NCT01183780.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Fluorouracil; Humans; Hypertension; Leucovorin; Neoplasm Metastasis; Prognosis; Ramucirumab; Randomized Controlled Trials as Topic; Survival Rate; Vascular Endothelial Growth Factor Receptor-2

Oxaliplatin is a key part of the standard treatment for colorectal cancer which is formally contraindicated in patients with severe renal dysfunction. Here, we investigated a safe and efficient dosing schedule of oxaliplatin in folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen by monitoring total and free platinum concentrations in plasma.. A 47-year-old female with chronic hemodialysis was diagnosed with left-sided colon cancer and underwent colectomy. One year later, she was presented with omentum metastasis and needed further treatment.. The computed tomography (CT) scanning revealed multiple omental nodules. Positron emission tomography-CT (PET-CT) showed increased uptake of the nodules.. The patient was treated with FOLFOX therapy every 3 weeks. The oxaliplatin began with 50 mg/m and gradually increased 85 mg/m as in the standard regimen. A 4-hour dialysis was started 1 hour after the end of oxaliplatin infusion.. The free platinum concentration time curve showed a biomodel pattern. The Cmax of the 1st peak we observed in our patients at the standard dose is comparable to patients with normal renal function. This patient was treated with FOLFOX for 12 courses. No apparent adverse effect was observed during the treatment.. The FOLFOX can be safely administered in hemodialysis patients on a long-term basis. Dose reduction of oxaliplatin is not necessarily needed if hemodialysis is performed soon after the infusion. Further studies are needed to distinguish between active and inactive oxaliplatin products during the 2nd peak of the free platinum concentration curve in this population.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chronic Disease; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Glomerulonephritis; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Renal Dialysis

Topics: Adult; Aged; Aged, 80 and over; Carboxylic Ester Hydrolases; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Genetic Association Studies; Germ-Line Mutation; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Neoplasm Metastasis; Polymorphism, Single Nucleotide

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Treatment Outcome

To investigate the efficacy of paclitaxel combined with a leucovorin and 5-fluorouracil regimen (PLF regimen; q2w) as neoadjuvant chemotherapy (NCT) for advanced gastric cancer.. A total of 183 patients with advanced gastric cancer who underwent 3 cycles of PLF regimen chemotherapy before surgery and received surgery 2 weeks after chemotherapy were enrolled as a treatment group. A total of 184 patients with advanced gastric cancer and no NCT during the same period were enrolled as the controls and treated with surgery. Both groups underwent a D2 radical gastrectomy and the standard postoperative adjuvant chemotherapy.. In the NCT group, there were 19 cases of complete remission, 86 cases of partial remission, 72 cases of stable disease, and 6 cases of progressive disease, with an overall response rate of 57.4%. The R0 resection rate was higher than in the control group (85.2% vs 61.4%,. The PLF regimen showed good tolerability and a high response rate, especially for esophagogastric cancer. This regimen reduced the tumor size, lowered the tumor stage, and improved the R0 resection rate and survival rate.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Paclitaxel; Retrospective Studies; Stomach Neoplasms; Survival Analysis; Treatment Outcome

The current analysis aims to provide an evaluation of the impact of diabetes mellitus (DM) on the efficacy and safety of first-line FOLFOX chemotherapy for patients with metastatic colorectal cancer (mCRC).. This is a pooled analysis of the comparator arms of two clinical trials (NCT00272051; NCT00305188) which evaluated first-line FOLFOX chemotherapy for patients with mCRC. The overall survival and progression-free survival according to patient subsets (non-diabetic and diabetic patients) were assessed through Kaplan-Meier analysis and log-rank testing. Propensity score matching was additionally conducted to account for heterogeneity in baseline characteristics of different subsets of patients.. A total of 756 patients were enrolled in the current analysis; of which 64 patients have pre-existing DM while 692 patients were non-diabetic. Through Kaplan-Meier analysis, no evidence for overall or progression-free survival difference was found among the two patient subsets (P = 0.501; P = 0.960, respectively). Moreover, metformin treatment does not affect overall or progression-free survival among diabetic patients (P = 0.598; P = 0.748, respectively). Repetition of overall and progression-free survival assessment following propensity score matching does not reveal any differences. Comparing diabetic to non-diabetic patients, there were no differences between the two groups in terms of acute oxaliplatin-induced neurological symptoms including cold-induced dysthesia (P = 0.600), laryngeal dysthesia (P = 0.707), jaw pain (P = 0.743) or muscle pain (P = 0.506). Moreover, no difference was seen between the two groups in terms of the incidence of long-term oxaliplatin-induced paresthesia (P = 0.107), highest grade of paresthesia (P = 0.498) or rates of recovery from paresthesia (P = 0.268). Diabetic patients have, however, a shorter time to develop oxaliplatin-induced paresthesia (P = 0.024).. DM does not seem to affect overall or progression-free survival of mCRC patients treated with first-line FOLFOX chemotherapy. Moreover, DM does not influence the incidence or severity of oxaliplatin-induced paresthesia in those patients while it might lead to a shorter time to develop oxaliplatin-induced paresthesia compared to non-diabetic patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Comorbidity; Diabetes Mellitus; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Propensity Score; Survival Rate; Treatment Outcome

Emerging evidence on the optimal use of chemotherapy and biologics in patients with metastatic colorectal cancer should impact management in routine care. Recent studies have demonstrated benefits for initial triplet chemotherapy (5-fluorouracil, oxaliplatin and irinotecan, FOLFOXIRI) and for initial treatment with an epidermal growth factor receptor inhibitor (EGFRi) in patients with a RAS wild-type tumour and a left-sided primary tumour.. To explore evolving pattern of metastatic colorectal cancer care over time in Australia.. We analysed data from the Treatment of Recurrent and Advanced Colorectal Cancer registry.. From July 2009 to December 2017, 2552 metastatic colorectal cancer patients were entered into the Treatment of Recurrent and Advanced Colorectal Cancer registry. Of 1585 patients who initially underwent chemotherapy, treatment was with a doublet in 76%. FOLFOXIRI was given to 22 patients (1.4%), mostly young patients and those with potentially resectable disease. Along with first-line chemotherapy, 61% received bevacizumab, while 3.3% received an EGFRi, predominantly over the last 2 years. Within the KRAS wild-type left-sided tumour cohort, EGFRi use increased from 9% in 2015 to 37% in 2017. Across treatment sites, there was a wide variation in the utilisation of FOLFOXIRI and EGFRi therapy; bevacizumab use was more consistent. A clear impact on survival outcomes from these regimens is not evident, potentially due to multiple confounders.. Doublet chemotherapy + bevacizumab remains the dominant initial strategy, with limited uptake of triplet chemotherapy and of EGFRi. Potential explanations include uncertainty about the significance of post hoc analyses for EGFRi and concerns regarding adverse events for both strategies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Australia; Bevacizumab; Biological Products; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Registries; Treatment Outcome; Young Adult

Irinotecan (CPT-11) is a drug used against a wide range of tumor types. The individualized dosing of CPT-11 is essential to ensure optimal pharmacotherapy in cancer patients, given the wide interindividual pharmacokinetic variability of this drug and its active metabolite SN-38. Moreover, the reabsorption from SN-38-G to SN-38, by enterohepatic recirculation, is critical due to its influence in the treatment tolerance. The aim of this research was to build a joint population pharmacokinetic model for CPT-11 and its metabolites (SN-38, and its glucuronide, SN-38-G) that enabled an individualized posology adjustment.. We used data of 53 treatment cycles of FOLFIRINOX scheme corresponding to 20 patients with metastatic colorectal cancer. In order to build the population pharmacokinetic model, we implemented parametric and non-parametric methods using the Pmetrics library package for R. We also built multivariate regression models to predict the area under the curve and the maximum concentration using basal covariates.. The final model was a multicompartmental model which represented the transformations from CPT-11 to its active metabolite SN-38 and from SN-38 to inactive SN-38-G. Besides, the model also represented the extensive elimination of SN-38-G and the reconversion of the remaining SN-38-G to SN-38 by enterohepatic recirculation. We carried out internal validation with 1000 simulations. The regression models predicted the PK parameters with R squared adjusted up to 0.9499.. CPT-11, SN-38, and SN-38-G can be correctly described by the multicompartmental model presented in this work. As far as we know, it is the first time that a joint model for CPT-11, SN-38, and SN-38-G that includes the process of reconversion from SN-38-G to SN-38 is characterized.

Topics: Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Glucuronates; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Models, Biological; Neoplasm Metastasis; Organoplatinum Compounds

Panitumumab is approved for RAS wild-type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first-line randomised studies. This retrospective analysis of these trials investigated efficacy and toxicity of panitumumab-based maintenance after oxaliplatin discontinuation in RAS wild-type patients. First-line regimens were FOLFOX4 ± panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression-free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5-fluorouracil/leucovorin (5-FU/LV) maintenance was 21 (interquartile range: 11-41) weeks; that of 5-FU/LV ± bevacizumab maintenance was 16 (6-31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3-50.4) and 39.1 (34.2-63.0) months for panitumumab plus 5-FU/LV maintenance and 24.1 (17.7-33.0) and 28.9 (21.0-32.0) months for 5-FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3-23.6) and 15.4 (11.6-18.4) months for panitumumab plus 5-FU/LV maintenance and 12.6 (9.4-16.2) and 13.1 (9.5-16.6) months for 5-FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7-42.8) and 33.5 (24.5-54.9) months for panitumumab plus 5-FU/LV maintenance and 16.4 (12.4-24.1) and 23.3 (15.7-26.3) months for 5-FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8-19.2) and 9.7 (5.8-14.8) months and 7.1 (5.6-10.2) and 7.0 (3.9-10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5-FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first-line treatment. Prospective studies are warranted.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Randomized Controlled Trials as Topic; Retrospective Studies; Survival Analysis; Treatment Outcome

This study aimed to better understand panitumumab use in real-life clinical practice in first- and second-line treatment of metastatic colorectal cancer in five European countries.. This is a combined analysis of two observational, non-interventional prospective cohort studies, one of which was conducted in Germany and France, the other in Bulgaria, Czech Republic, and Hungary. The studies observed patients with wild-type [Kirsten] rat sarcoma viral oncogene homolog ([K]RAS/RAS) metastatic colorectal cancer (mCRC), who had been treated with panitumumab in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in the first line or with panitumumab combined with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the second line following fluoropyrimidine-based chemotherapy. The planned duration of observation was 12 months from the first dose of panitumumab.. A total of 332 patients treated with panitumumab + FOLFOX in the first line and 94 patients treated with panitumumab + FOLFIRI in the second line were analyzed. The median number of panitumumab infusions was 10.0 in first-line FOLFOX patients and 11.5 in second-line FOLFIRI patients; the median duration of panitumumab exposure was 5.7 and 6.9 months, respectively. The unadjusted overall response rate (complete or partial response) in patients with available post-baseline response assessment (n = 290) was 51.7% in first-line FOLFOX and 44.9% in second-line FOLFIRI patients. In the first-line setting, resectability was achieved in 9.3%. Reported hospitalizations were mostly cancer-related visits such as scheduled anticancer treatment administrations, tumor assessment visits, or interventions. The majority of adverse drug reactions were skin disorders, with 75.3% in first-line FOLFOX patients and 72.3% in second-line FOLFIRI patients.. Overall, the study results show that treatment patterns, clinical efficacy, and the safety profile of panitumumab in routine clinical practice were comparable to those in randomized controlled trials. The relatively low skin toxicity rate could be attributed to increasing experience in managing panitumumab-associated rash and some degree of underreporting.. Amgen.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Colorectal Neoplasms; Europe; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Prospective Studies; ras Proteins

To evaluate the pattern of tumor relapse of pathological complete response (pCR) patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME), and to identify predictive factors of distant metastasis in pCR patients after nCRT.. This was a retrospective analysis of 118 LARC patients who achieved a pCR following nCRT and TME from 2008 to 2015. Clinicopathological and therapeutic parameters were evaluated as possible predictors of distant metastasis-free survival (DMFS), and COX regression analysis was performed.. After a median follow-up of 57 months, the 5-year overall and disease-free survival rates were 94.7% and 88.1%, respectively. Overall, 6 patients (5.1%) died, no local recurrence occurred, 13 patients (11%) developed distant metastases, including lung (n = 5), liver (n = 2), bone (n = 3), lung and brain (n = 1), peritoneal (n = 1), and spleen (n = 1) metastasis. On univariate analysis, tumor distance from the anal verge (HR = 0.706, P = 0.039), acellular mucin pools (HR = 6.687, P = 0.002), and MUC1 expression (HR = 8.280, P < 0.001) were independently associated with DMFS. COX regression demonstrated that MUC1 expression (HR = 3.812, P = 0.041) remained to be an independent predictor of DMFS in pCR patients.. Distant metastasis still remained a major concern in pCR patients following nCRT and TME. Tumor distance from the anal verge, acellular mucin pools, and MUC1 expression were associated with distant metastasis in patients with pCR. MUC1 staining remained to be an independent risk factor for DMFS. Such information could facilitate treatment decision in these patients, such as adjuvant chemotherapy and follow-up.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Capecitabine; Chemoradiotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Humans; Incidence; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Mesentery; Middle Aged; Mucin-1; Mucins; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Proctectomy; Proportional Hazards Models; Rectal Neoplasms; Remission Induction; Retrospective Studies; Splenic Neoplasms

The prognostic value of vascular endothelial growth factor-A (VEGFA) and epithelial cadherin (E-cadherin) expression in patients with metastatic colorectal cancer (mCRC) is controversial.. In this prospective study, patients diagnosed with mCRC between August 1, 1998, and August 30, 2003, at the Turku University Hospital, Finland were included. Expression of E-cadherin (membranous and cytoplasmic pattern) and VEGFA in tumour samples was assessed by immunohistochemistry. Tumours were classified as E-cadherin expressers if they demonstrated moderate or strong cytoplasmic or membranous staining, while those positive for VEGFA expression showed a moderate or strong cytoplasmic staining. Of particular interest was the association between membranous or cytoplasmic expression of E-cadherin and VEGFA. The value of strong VEGF-A staining and membranous or cytoplasmic expression of E-cadherin as a predictor of disease outcome over a 6-year period was another point of interest in this study.. Of the 67 patients with mCRC, 43 (64%) had tumours positive for cytoplasmic E-cadherin, while in 24 cases (36%), E-cadherin expression was membranous. Strong VEGFA staining was present in half of the cases (n=36, 54% of all 67 mCRC cases). VEGFA expression was significantly correlated with cytoplasmic E-cadherin expression in that 28/36 cases of VEGFA-positive tumours were also positive for cytoplasmic E-cadherin (p=0.012). In addition, among the patients with intense VEGFA expression (n=36), those who had positive cytoplasmic E-cadherin in their tumours had a lower response-rate to first-line therapy with irinotecan, fluorouracil and leucovorin regimen: 5 out of 36 (14%) were chemosensitive. This is in contrast to the patients with VEGFA-positive tumours and membranous E-cadherin (8/36, 22% chemosensitive (p=0.004). The former group also had more ominous prognosis (p<0.001).. Reduced membranous expression of E-cadherin and increased cytoplasmic E-cadherin expression predict poor survival in mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cadherins; Cell Membrane; Colorectal Neoplasms; Cytoplasm; Female; Finland; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Catheterization, Central Venous; Central Venous Catheters; Colorectal Neoplasms; Epidural Space; Fatal Outcome; Fluorouracil; Humans; Iatrogenic Disease; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Paraplegia; Spinal Cord; Spinal Cord Diseases

Effective chemotherapy protocols are currently changing the treatment options for metastasized pancreatic cancer. Survival benefits after synchronous metastasectomy have been reported for selected patients. We set out to assess predictive factors of resectability for synchronous metastases after FOLFIRINOX.. Consecutive patients with metastatic pancreatic cancer undergoing surgery after FOLFIRINOX between 2011 and 2017 were identified from a prospectively collected database. Surgery following chemotherapy was indicated in patients with no more than six metastatic lesions, no progression detected on CT, and technically resectable disease. Patients who received synchronous metastasectomy were compared with patients who received explorative laparotomy or palliative surgery in terms of predictors of resectability and overall survival. In patients undergoing resection, prognostic factors were examined.. Of 101 patients scheduled for surgery after FOLFIRINOX, synchronous metastasectomy was performed in 43 cases (43%) and non-resection surgery in 58 cases (57%). The shrinkage rate of the primary tumor on CT (P = 0.04) and the postchemotherapy serum CA19-9 concentration (P = 0.02) were associated with resectability. The median overall survival of the patients undergoing metastasectomy was longer than that of the patients without resection (21.9 months vs 16.4 months, P = 0.006). Postchemotherapy serum CA19-9 value (P = 0.04) and lymph node ratio (P = 0.01) were prognostic factors in the patients undergoing metastasectomy.. In selected patients who satisfied our surgical criteria, shrinkage rate of primary tumor and postchemotherapy serum CA19-9 level, which predict resectability of metastasized pancreatic cancer, should be considered in decision making to avoid unnecessary surgery.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoma, Pancreatic Ductal; Cohort Studies; Databases, Factual; Disease-Free Survival; Female; Fluorouracil; Germany; Humans; Induction Chemotherapy; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Metastasectomy; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Patient Selection; Prognosis; Proportional Hazards Models; Retrospective Studies; Survival Analysis; Tomography, X-Ray Computed

Few data of folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab (RAM) obtained in bevacizumab-naïve patients in clinical trials or routine clinical practice are available. The purpose of this retrospective study was to report the results of FOLFIRI plus RAM treatment as second-line chemotherapy for metastatic colorectal cancer (mCRC).. Seventy-four patients with mCRC who received second-line FOLFIRI + RAM mCRC therapy were stratified by previous first-line therapy to groups that had (PB) or had not (NPB) been given bevacizumab. The overall survival (OS), progression-free survival (PFS), and objective response were evaluated.. The overall median PFS was 6.2 months (95% CI 4.6-9.3) and median OS was 17.0 months (95% CI 11.6-NA). Median PFS was 8.0 months (95% CI 4.9-11.2) in NPB patients and 5.0 months (95% CI 3.1-7.3) in PB patients (hazard ratio = 0.72, 95% CI 0.40-1.30, p = 0.28). The response rates were 23% and 3% in NPB and PB patients, respectively. The disease control rates were 85% and 69% in NPB and PB patients, respectively.. The effectiveness of FOLFIRI + RAM as a second-line chemotherapy in patients with mCRC was in line with that reported in the previous RAISE phase III trial. The response was better in bevacizumab-naïve patients than those with first-line treatment that had included bevacizumab.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cohort Studies; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Ramucirumab; Retrospective Studies

We report a case of metastatic pancreatic-head mucinous carcinoma (with multiple lymph node and bone metastases) and review the relevant literature. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was useful for diagnosis, and a satisfactory outcome was achieved after systemic chemotherapy with FOLFIRINOX followed by resection of the primary lesion as conversion surgery. The patient was a 55-year-old man. Hematological findings included elevated serum tumor marker levels: CEA 12.7 ng/mL, DUPAN-2 400 U/mL. Findings from several imaging modalities and EUS-FNA confirmed a clinicopathological diagnosis of metastatic pancreatic mucinous carcinoma with multiple bone and lymph node metastases. Five courses of modified FOIFIRINOX (m-FFX) were given as systemic chemotherapy, which had an antitumor effect. Subtotal stomach-preserving pancreaticoduodenectomy and extensive lymph-node dissection were thus performed. Histopathological analysis showed invasive ductal carcinoma, muc (pT3, pN1b, cM1). After surgery, the clinical course was notable for the absence of complications. Tegafur/gimeracil/oteracil (S-1) was started as maintenance adjuvant chemotherapy postoperatively, and no disease progression has been observed at 10 months after surgery.

Topics: Adenocarcinoma, Mucinous; Antineoplastic Combined Chemotherapy Protocols; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Fluorouracil; Humans; Irinotecan; Leucovorin; Lymph Nodes; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Tomography, X-Ray Computed

Spontaneous cancer regression is a rare event, scarcely reported among gastrointestinal malignancies. Pancreatic adenocarcinoma regression has been documented in five previous cases, none of which included liver metastases, and the mechanism by which this occurs is not known. A 56-year-old woman with history of discoid lupus, homocysteinemia and peripheral vascular disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDA) metastatic to the liver. She received palliative chemotherapy with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) for 6 months, complicated by mucositis, diarrhoea, vomiting and two

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lupus Erythematosus, Discoid; Middle Aged; Neoplasm Metastasis; Neoplasm Regression, Spontaneous; Oxaliplatin; Pancreatic Neoplasms

Sarcopenia, the presence of skeletal muscle mass depletion, can be objectively quantified, whereas subjective global assessment (SGA) is a widely utilized subjective instrument to assess nutritional status. Both the presence of sarcopenia and SGA-assessed malnutrition, in isolation, have been shown to be associated with worse overall survival in a wide range of cancers. However, there is no research evaluating the independent prognostic significance of both the presence of sarcopenia and malnutrition as part of the same analysis. We investigated the impact of sarcopenia on overall survival in colorectal cancer specifically controlling for malnutrition.. We examined a consecutive case series of 112 patients with colorectal cancer first seen at our institution between August 2012 and October 2017. Using computed tomography (CT) imaging, the cross-sectional area of muscles at the L3 vertebral level was measured and then divided by height squared to calculate skeletal muscle index (SMI). Sarcopenia was defined as SMI ≤38.5 cm2/m2 for women and ≤52.4 cm2/m2 for men. SGA assessments were completed within 2 weeks of CT imaging. The association of sarcopenia and malnutrition with overall survival was assessed using univariate and multivariate Cox regression analysis.. Median age at presentation was 53.3 years. Sixty-six (58.9%) patients had metastatic disease at diagnosis. Using SMI, 46 (41.1%) patients were sarcopenic, while 66 (58.9%) were non-sarcopenic. Using SGA, 69 (61.6%) patients were assessed as well-nourished, while 43 (38.4%) were malnourished. Of 69 patients classified as well-nourished by SGA, 22 (31.9%) were sarcopenic. Similarly, of 43 patients categorized as malnourished by SGA, 19 (44.2%) were non-sarcopenic. On multivariate analysis, after adjusting for age, gender, tumor stage, BMI, treatment history and SGA, patients with sarcopenia had 3 times greater risk of mortality compared to those without sarcopenia (p = 0.001). The median survival of patients with both sarcopenia and malnutrition (n = 24) was 14.6 months (95% CI: 10.5 to 18.6) compared to the median survival of 25.9 months (95% CI: 7.8 to 44.0) in patients who were either sarcopenic or malnourished but not both (n = 41; p = 0.001). The median survival of patients who were non-sarcopenic and well nourished (n = 48; p = 0.001) was 38.6 months (95% CI: 25.6 to 51.6).. The exploratory study suggests that presence of sarcopenia supersedes the presence of malnutrition as a predictor of survival in colorectal cancer. Co-existence of sarcopenia and malnutrition is associated with worse survival in colorectal cancer compared to just one of those conditions being present. Prospective studies with large sample sizes are needed to confirm these findings.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Predictive Value of Tests; Prognosis; Retrospective Studies; Risk Factors; Sarcopenia; Survival Analysis

The aim of this study was to investigate the effects of preoperative chemotherapy on the healthy, metastasis-free part of the liver in colorectal cancer patients with liver metastasis, and the relationship between chemotherapy and postoperative complications.. Our study included 90 cases of colorectal cancer liver metastasis resected after preoperative chemotherapy. The patients were divided into three groups according to the received chemotherapy regimen: 20 cases received mFOLFOX6, 54 cases a combination of mFOLFOX6 with bevacizumab, and 16 cases a combination of mFOLFOX6 and cetuximab or panitumumab.. The mean numbers of sinusoidal injuries for each chemotherapy type were compared. The group treated with the combination of mFOLFOX6 and bevacizumab showed a lower extent of sinusoidal injury relative to other groups; this intergroup difference became increasingly remarkable as the number of chemotherapy cycles increased. Complications of various extents were found in all three groups, but no significant differences were observed between the three groups.. In cases where preoperative chemotherapy was extended over a long period, combined use of bevacizumab was thought to be effective because of stabilization of disturbed liver hemodynamics resulting from sinusoidal injury suppression effects, allowing effective distribution of anti-cancer agents to tumors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Postoperative Complications; Preoperative Period

We conducted this study to assess the effect of baseline body mass index (BMI) on the toxicity and efficacy of systemic chemotherapy among patients with metastatic colorectal cancer (CRC).. This was a pooled analysis of 5 clinical trials (NCT00115765, NCT00364013, NCT00272051, NCT00305188, and NCT00384176), which were accessed from the Project Data Sphere (www.projectdatasphere.org) platform. Multivariable logistic regression analysis was used to assess the relationship between BMI and the probability of different toxicities. Kaplan-Meier survival estimates were used to assess the effect of BMI on overall and progression-free survival. Multivariable Cox regression analysis was additionally conducted to evaluate the effect of BMI on overall and progression-free survival.. A total of 3155 patients were included in the current analysis. Within multivariable logistic regression analysis, higher BMI was associated with higher probability of all-grade nausea and vomiting (odds ratio [OR], 1.025; 95% confidence interval [CI], 1.009-1.042; P = .002) and peripheral neuropathy (OR, 1.018; 95% CI, 1.001-1.034; P = .036; analysis restricted to oxaliplatin-treated patients). Lower BMI was associated with a higher probability of all-grade anemia (OR, 0.975; 95% CI, 0.956-0.995; P = .015), high-grade anemia (OR, 0.941; 95% CI, 0.890-0.994; P = .030), all-grade neutropenia (OR, 0.983; 95% CI, 0.968-0.999; P = .034), and high-grade neutropenia (OR, 0.962; 95% CI, 0.945-0.979; P < .001). Higher BMI also seemed to correlate with better overall survival in a multivariable Cox regression model (hazard ratio as a continuous variable: 0.977; 95% CI, 0.967-0.988; P < .001).. Lower BMI was associated with a higher risk of hematological toxicities (anemia and neutropenia) whereas higher BMI might be associated with a higher risk of nausea, vomiting, and peripheral neuropathy. Higher BMI also seemed to be associated with better overall survival among patients with metastatic CRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Canada; Colorectal Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Follow-Up Studies; Humans; Incidence; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Panitumumab; Prognosis; Randomized Controlled Trials as Topic; Retrospective Studies; Survival Rate

Studies on the effects of third-line chemotherapy (CT) in advanced gastric cancer (GC) patients are still scarce. The aim of this study was to evaluate the efficacy and safety of the modified 5-fluorouracil, leucovorin, and irinotecan (mFOLFIRI) regimen as a third-line CT in metastatic GC patients, after failure of fluoropyrimidine, platinum, anthracycline, and taxane. After failure of first- and second-line therapies, 42 patients received third-line FOLFIRI (180 mg/m² irinotecan and 400 mg/m² leucovorin administered concomitantly as a 90-minute intravenous (IV) infusion on day 1, followed by a 400 mg/m² 5-fluorouracil IV bolus then 2600 mg/m² continuous infusion over 46 hours), between January 2009 and December 2015. FOLFIRI was administered for a median of 6 cycles (range 4-12 cycles). Eight patients achieved partial response, while 13 patients showed stable disease, resulting in the overall response rate (ORR) of 19% and disease control rate (DCR) of 50%. The most frequent grade 3-4 hematological and non-hematological toxicities were neutropenia (14.2%) and diarrhea (7.1%). The median progression-free survival (PFS) and overall survival (OS) from the start of third-line CT were 3.8 months (95% confidence interval [CI], 3.0-4.5) and 6.8 months (95% CI, 5.6-7.9), respectively. According to the multivariate analysis, two factors were independently predictive of the poor OS: >2 regions of metastasis (relative risk [RR], 2.6; 95% CI, 1.3-5.4) and a high level of carcinoembryonic antigen [CEA] (RR, 3.4; 95% CI, 1.6-7.4). In conclusion, FOLFIRI was well tolerated as third-line CT and showed promising PFS and OS in advanced GC patients, after failure of fluoropyrimidine, platinum, anthracycline, and taxane.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Female; Fluorine; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Patient Safety; Platinum; Pyrimidines; Stomach Neoplasms; Taxoids; Treatment Outcome

Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI), portal hypertension, and splenic sequestration of platelets. Evidence suggests that bevacizumab may protect against HSI.. Two cohorts of metastatic colorectal cancer (CRC) were analyzed: a nonrandomized exploratory cohort of 184 patients treated at a single institution from 2003 to 2010 and a confirmatory cohort of 200 patients from a multi-institutional randomized trial (NO16966). All patients were treated with frontline fluoropyrimidine and oxaliplatin with or without bevacizumab. Changes in splenic volumes and platelet counts were compared by treatment, two-sided log-rank test.. In the exploratory cohort, the bevacizumab-treated patients (n = 138) compared with the nonbevacizumab-treated patients (n = 46) demonstrated a longer median time to splenic enlargement (≥30%, P = .02) and reduced rate of thrombocytopenia (<150 000/mm3, P = .04). In the confirmatory cohort (106 bevacizumab arm and 94 placebo arm), the median time to a spleen enlargement of 30% or more was 7.6 vs 5.4 (P = .01), and six-month cumulative incidence of thrombocytopenia (platelets < 100 000/mm3) was 19% vs 51% (P < .001) for bevacizumab compared with placebo. The development of an increasing spleen size was associated with the risk of either grade 1 or grade 2 thrombocytopenia (P < .001). The cumulative rate of grade 1 or grade 2 thrombocytopenia was statistically less in the bevacizumab arm, with six-month grade 2 thrombocytopenia rates of 4% vs 23% (P < .001). Patients with a large spleen prior to chemotherapy initiation appeared to be at highest risk of this toxicity.. In metastatic CRC, the addition of bevacizumab to oxaliplatin-based chemotherapy reduces the frequency of splenic enlargement and the rate of thrombocytopenia.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver; Male; Middle Aged; Multicenter Studies as Topic; Neoplasm Metastasis; Organ Size; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Retrospective Studies; Spleen; Thrombocytopenia

Pancreatic cancer (PC) has a very low average survival, but its prognosis is further reduced in the case of metastatic spread. Medical therapy in these cases is the only applicable methodology in the international guidelines. During anticancer treatments, common side effects are nausea, vomiting, arthralgia, neuropathy, and alopecia as well as a myelosuppressive effect. The toxicity of various drugs not only affects the quality of life of the patient, but often its severity requires a reduction in if not the termination of drug administration. Scientific studies have shown that a combined use of chemotherapy and certain natural substances, in the form of standardized extracts, can lead to an enhancement of the action of the chemotherapy. Here, we describe 2 cases of metastatic PC. The first case concerns the integrated treatment of a patient with cancer of the pancreas tail with metastatic involvement ab initio of peripancreatic lymph nodes and liver parenchyma, with numerous secondary lesions greater than 9.5 cm. The second case concerns the integrated treatment of a patient with cancer of the pancreatic body with metastatic involvement of the liver parenchyma, with a small secondary lesion. In both cases, an integrated cancer treatment approach, combining chemotherapy with natural remedies, extracts, and hyperthermia, induced a notable remission of primary and metastatic lesions.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Combinations; Female; Fluorouracil; Humans; Hyperthermia, Induced; Integrative Oncology; Irinotecan; Leucovorin; Middle Aged; Mind-Body Therapies; Neoplasm Metastasis; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Phytotherapy; Remission Induction; Treatment Outcome

A 44-year-old woman with advanced metastatic colon cancer received chemotherapies comprising oxaliplatin and capecitabine (XELOX), irinotecan hydrochloride, leucovorin calcium and fluorouracil irinotecan (FOLFIRI)/panitumumab and mFOLFOX6/bevacizumab. Fifteen months later, she presented with the acute onset of a headache, drowsiness and seizure with a fever and hypertension. Brain magnetic resonance imaging (MRI) indicated bilateral regions of signal hyperintensity in the white matter with spasms of bilateral cerebral arteries apparent on magnetic resonance angiography. Posterior reversible encephalopathy syndrome (PRES) was diagnosed, and treatments resulted in improvement of the MRI findings, but the patient experienced cerebral infarction and ultimately died of deterioration of cancer on day 26 after the onset of PRES.

Topics: Adult; Antineoplastic Agents, Immunological; Bevacizumab; Camptothecin; Capecitabine; Colonic Neoplasms; Female; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Posterior Leukoencephalopathy Syndrome; Treatment Outcome

The aim of this study was to investigate the efficacy and safety of first-line panitumumab plus folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) in patients with wild-type KRAS and wild-type NRAS metastatic colorectal cancer (mCRC).. Patients with wild-type KRAS and wild-type NRAS mCRC presenting to the medical oncology department of the Okmeydani Training and Research Hospital in Istanbul, Turkey, between April 2014 and January 2018 were enrolled in this study.. A total of 64 patients (35 males and 29 females) with a median age of 59 (35-81) years old were enrolled. The median follow-up was 18.9 months, and the median progression-free survival was 13 months. The median overall survival (OS) was 26 months in the patients with wild-type KRAS and wild-type NRAS mCRC. It was 90.4% for the 6-month OS, 79.5% for the 1-year OS, 53.7% for the 2-year OS and 31.1% for the 3-year OS. The median OS of the patients who underwent metastasectomies was 40 [95% confidence interval (CI) = 19.9-60.1] months, and the median OS of the patients without metastasectomies was 22 (95% CI = 17.7-26.4) months. There was a statistically significant difference between these (P = 0.007).. The first-line FOLFIRI plus panitumumab was associated with favourable efficacy in the patients with wild-type KRAS and wild-type NRAS mCRC, and it was well tolerated. The removal of the metastases that became resectable after chemotherapy further prolonged the patients' survival.. Retrospectively registered: 33886.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; GTP Phosphohydrolases; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Male; Membrane Proteins; Middle Aged; Mutation; Neoplasm Metastasis; Panitumumab; Prognosis; Proto-Oncogene Proteins p21(ras); Survival Rate

5-Fluorouracil (5FU), Folinic acid (FA), and Oxaliplatin (FOLFOX) or 5FU, FA, and Irinotecan (FOLFIRI) are standard regimens for palliative chemotherapy of metastatic colon cancer. Since data showing the influence of dose reduction in palliative treatment are rare, the objective of this single center, retrospective study was to further characterize the influence of dose reduction on efficacy of these therapeutic regimens.. One hundred nine patients, diagnosed with stage IV colon cancer between 2004 and 2012 and receiving palliative first-line chemotherapy with either FOLFOX or FOLFIRI regimens in our outpatient clinic were analyzed for treatment efficacy. Patients who received dose reductions due to side effects usually received doses of 80% or lower of per protocol dose. Survival data were obtained from the Regensburg Tumor Registry. Survival analysis was performed using Kaplan-Meier statistical analysis and multivariable analysis.. A dose reduction due to side effects was necessary in 46 (42%) patients. Dose reduction was independent of age. Major reasons for dose reduction were neutropenia (30%) followed by polyneuropathy (16%) and diarrhea (14%). Dosage was more often reduced in patients receiving FOLFOX based therapy. Comparison of patients with dose reduction versus patients with full dosage showed no significant difference on overall survival (p = 0.430). Subgroup analysis revealed dose reduction in patients with N2 stage disease was associated with improved survival. Patients who underwent dose reduction received more cycles of chemotherapy (13.7 vs. 10.8 cycles) and cumulative dosage was similar in both groups.. Contrary to our expectations, the need to reduce chemotherapy dosage due to side effects does not indicate a worse prognosis in our retrospective analysis. We believe this can in part be explained by better adaption to interindividual pharmacokinetics and longer time of treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Palliative Care; Prognosis; Proportional Hazards Models; Retrospective Studies; Treatment Outcome

New chemotherapies have become available for the treatment of advanced pancreatic cancer and have led to changes in its standard treatments. Since pancreatic cancer is becoming more common as a result of population aging, there is a need for diversification of chemotherapy.. Between March 2014 and April 2017, FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (G-nab) was used as first-line therapy to treat 27 patients with locally advanced and metastatic pancreatic cancer at our hospital. In this study, we retrospectively evaluated their clinical characteristics, survival outcomes and adverse events.. Twelve of the 27 patients were treated with FFX, and the other 15 patients were treated with G-nab. The disease control rate was 86.7% in the G-nab group and 75% in the FFX group. Median OS time was 8.9 months in the FFX group and 11.8 months in the G-nab group. The 1-year survival rate was 46.6% in the G-nab group and 16.6% in the FFX group. The second-line treatment rate was 40% in the G-nab group and 66.7% in the FFX group. The grade 3-4 neutropenia rate was 20% in the G-nab group and 25% in the FFX group. No patients developed febrile neutropenia, or severe nausea, diarrhea, or anorexia. The peripheral sensory neuropathy rate was 73.3% in the G-nab group and 75% in the FFX group.. Although G-nab and FFX are effective treatments for advanced pancreatic cancer, the G-nab group had a higher 1-year survival rate, and G-nab can be more safely administered to older patients.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Survival Rate

There is limited data on third-line chemotherapy in patients with metastatic gastric cancer (MGC). This study was conducted to assess third-line treatment patterns, outcomes, and clinical parameters related to survival outcomes in patients with MGC.. Using the Korean Health Insurance Review and Assessment Service (HIRA) database, a nationwide population-based outcomes study was conducted. From the HIRA database, patients newly diagnosed in 2010 with MGC were identified (N = 1,871), and of these, 229 patients who had received third-line chemotherapy were finally selected for this study.. Prior to third-line chemotherapy, more than 90% of patients received fluoropyrimidine and platinum, and 43.7% and 40.6% received taxane and irinotecan, respectively. Various third-line chemotherapy regimens containing taxane (docetaxel or paclitaxel), irinotecan, or oxaliplatin were prescribed. The median overall survival (OS) of all patients receiving third-line chemotherapy was 4.4 months. The median time from the start date of first-line chemotherapy to the start date of third-line chemotherapy (TF1T3) was 9.5 months, and a longer TF1T3 was the only factor that was significantly associated with an increased OS. The median OS of patients who had received fluoropyrimidine, platinum, and taxane followed by third-line irinotecan-based therapy was similar to that of patients who had received fluoropyrimidine, platinum, and irinotecan followed by third-line taxane-based therapy (p = 0.894).. In patients with MGC receiving third-line chemotherapy, TF1T3 was the only significant factor associated with OS. The sequence of using taxane and irinotecan as subsequent therapy after first-line failure was not shown to impact survival outcome.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Databases, Factual; Disease-Free Survival; Docetaxel; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Stomach Neoplasms; Treatment Outcome

Gemcitabine (GEM), oxaliplatin plus GEM (OX + GEM), cisplatin plus GEM (CIS + GEM), capecitabine plus GEM (CAP + GEM), FOLFIRINOX (FFX), and nab-paclitaxel plus GEM (NAB-P + GEM) are the most commonly used regimens as first-line treatment of metastatic pancreatic cancer (MPC) in the UK. Independent economic evaluation of these regimens simultaneously has not been conducted for the UK.. Using data from a network meta-analysis as efficacy measures, we estimated the cost effectiveness and cost utility of these regimens for the UK.. A three-state Markov model (progression-free, progressed-disease, and death) simulating the total costs and health outcomes (quality-adjusted life-years [QALYs] gained and life-years [LYs]) was developed to estimate the incremental cost-utility (ICUR) and incremental cost-effectiveness ratios (ICER) for patients with MPC, from the payer perspective. The model was specified to calculate total costs in 2017 British pounds (GBP, £). All values were discounted at 3.5% per year over a full lifetime horizon. One-way sensitivity and probabilistic sensitivity analyses were conducted to assess the impact of parameter uncertainty on the results.. FFX was the most effective regimen, NAB-P + GEM was the most costly regimen, and GEM was the least costly and least effective regimen. OX + GEM, CIS + GEM, and NAB-P + GEM were dominated by CAP + GEM and FFX. Compared with GEM, the ICUR for CAP + GEM and FFX was £28,066 and £33,020/QALY gained, respectively; compared with GEM, the ICER for CAP + GEM and FFX was £17,437 and £22,291/LY gained, respectively; and compared with CAP + GEM, the ICUR and ICER for FFX were £34,947/QALY gained and 24,414/LY gained, respectively.. At a threshold value of £30,000/QALY, CAP + GEM was found to be the only cost-effective regimen in the management of MPC in the UK.

Topics: Adult; Albumins; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cisplatin; Cost-Benefit Analysis; Deoxycytidine; Disease Progression; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Markov Chains; Neoplasm Metastasis; Network Meta-Analysis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Quality-Adjusted Life Years; United Kingdom

Impact of time to start first-line systemic chemotherapy following diagnosis of metastatic colorectal cancer (mCRC) needs to be studied.. This is a pooled analysis of the raw data of the comparator arms of two randomized studies (NCT00272051; NCT00305188). Univariate and multivariate analyses of predictors of overall and progression-free survival were conducted through Cox regression analysis. Factors with statistically significant P value (P < 0.05) in the univariate part of the analysis were included in the multivariate analysis.. In univariate analysis, time to start systemic therapy did not affect overall or progression-free survival (P=0.694; P= 0.891 respectively). In multivariate analysis for overall survival, the following factors were predictive of worse overall survival: younger age (P = 0.019), higher ECOG performance score (P = 0.001), more than one site of metastatic disease (P = 0.002), colon site of the primary tumor (P = 0.004), and no oncologic surgery to the primary tumor (P < 0.001). Likewise, in multivariate analysis for progression-free survival, the following factors were predictive of worse progression-free survival: no oncologic surgery to the primary (P < 0.001), more than one organ of metastatic disease (P < 0.001), and no concurrent bevacizumab administration (P = 0.015).. Time to start systemic chemotherapy does not appear to impact overall or progression-free survival among mCRC patients.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colon; Colorectal Neoplasms; Female; Fluorouracil; Health Status; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Progression-Free Survival; Randomized Controlled Trials as Topic; Survival Rate; Time-to-Treatment; Treatment Outcome; Young Adult

RAS- or BRAF-mutated metastatic colorectal cancers (mCRCs) progressing after first-line treatment have a poor prognosis.European and U.S. guidelines include the multikinase inhibitor regorafenib as a standard option for second-line therapy and beyond, based on the results of the randomized phase III CORRECT trial demonstrating improvement in survival.Although stopped prematurely for failing to accrue, the PREVIUM trial, the first prospective interventional study exploring regorafenib as second-line treatment for patients with mCRC bearing RAS or BRAF mutations, failed to demonstrate clinical activity in the population analyzed.. Patients with RAS- or BRAF-mutated (mut) metastatic colorectal cancer (mCRC) progressing on first-line bevacizumab plus 5-FU/irinotecan/oxaliplatin (FOLFOXIRI) have a poor prognosis. We aimed to assess the efficacy and safety of regorafenib in this population.. Regorafenib was administered daily for 3 weeks of each 4-week cycle until disease progression or other reason. The primary endpoint was 6-month progression-free survival (PFS).. KRAS, NRAS, or BRAF was mutated in mCRC samples in 60%, 20%, and 13% of patients, respectively. Median time from initial diagnosis of metastases to the start of regorafenib and treatment duration was 13.8 months and 7 weeks, respectively. Reasons for discontinuation included disease progression (80%), investigator decision (13%), and adverse events (AEs; 7%). Seven patients (47%) required dose reduction, mostly for asthenia (43%). The most common regorafenib-related grade 3 AEs were asthenia (33%), dysphonia (13%), and hypertension (13%) (Table 1). There were no grade 4 toxicities. No patient was progression-free at 6 months. Median PFS, time to progression (TTP), and overall survival (OS) were 2.2, 2.0, and 3.3 months, respectively.. Although stopped prematurely for failing to accrue, in the population analyzed, regorafenib failed to demonstrate clinical activity in KRAS- or BRAF-mutated mCRC with progression following first-line with FOLFOXIRI plus bevacizumab, although tolerability was acceptable. Our trial suggests that exploring regorafenib efficacy in an earlier line of therapy should not be undertaken without better population refinement.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Phenylurea Compounds; Proto-Oncogene Proteins B-raf; Pyridines; ras Proteins

Therapy-related myelodysplasticsyndrome(t-MDS)has been reported to occur after treatment with cytotoxic agents and radiation. Here, we report a case of t-MDS following oxaliplatin(L-OHP)exposure, which was successfully treated with azacitidine(AZA). A 71-year-old man was referred to our department because of pancytopenia. He had been diagnosed with rectal cancer(cT4aNXM0, stage II B-III C, RAS gene status wild-type)3 years ago and had received 8 courses of capecitabine(CAP)and L-OHP(XELOX regimen), followed by 48 courses of CAP and bevacizumab. Before referral, recurrence of rectal cancer was detected using CT after the last course of chemotherapy. A bone marrow examination revealed multilineage dysplasia and 9.0%myeloblasts. Cytogenetic analysis disclosed a chromosome 7 abnormality. The diagnosis of t- MDS was made and treatment with AZA was initiated. Subsequently, temporary but significant hematological improvements were observed, which enabled the patient to receive additional palliative radiation therapy against the locally relapsed rectal cancer. AZA might be useful in t-MDS because of its efficacy and low toxicity.

Topics: Aged; Antimetabolites, Antineoplastic; Azacitidine; Combined Modality Therapy; Fatal Outcome; Humans; Leucovorin; Male; Myelodysplastic Syndromes; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms

The use of circulating tumor cells (CTCs) as indicators of treatment response in metastatic colorectal cancer (mCRC) needs to be clarified. The objective of this study is to compare the Response Evaluation Criteria in Solid Tumors (RECIST) with the Cytologic Criteria Assessing Response (CyCAR), based on the presence and phenotypic characterization of CTCs, as indicators of FOLFOX-bevacizumab treatment response.. 77 mCRC blood samples from FOLFOX-bevacizumab treated patients were analyzed to isolate CTCs before and after (12 and 24 weeks) treatment, using an immunomagnetic separation method. VEGFR expression was identified by double immunostaining.. We observed a decrease of CTCs (42.8 vs. 18.2%) and VEGFR positivity (69.7% vs. 41.7%) after treatment. According to RECIST, 6.45% of the patients did not show any clinical benefit, whereas 93.55% patients showed a favorable response at 12 weeks. According to CyCAR, 29% had a non-favorable response and 71% patients did not. No significant differences were found between the response assessment by RECIST and CyCAR at 12 or 24 weeks. However, in the multivariate analysis, RECIST at 12 weeks and CyCAR at 24 weeks were independent prognostic factors for OS (HR: 0.1, 95% CI 0.02-0.58 and HR: 0.35, 95% CI 0.12-0.99 respectively).. CyCAR results were comparable to RECIST in evaluating the response in mCRC and can be used as an alternative when the limitation of RECIST requires additional response analysis techniques.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Neoplastic Cells, Circulating; Organoplatinum Compounds; Prognosis; Proportional Hazards Models; Receptors, Vascular Endothelial Growth Factor; Reference Standards; Response Evaluation Criteria in Solid Tumors; Treatment Outcome

The benefit of IFL (irinotecan, fluorouracil and leucovorin) regimen for metastatic colorectal cancer patients (mCRCs) with high levels of microsatellite instability (MSI-H) or loss of mismatch repair (dMMR) protein expression, is uncertain. This study investigated the association of tumour MMR-status and VEGF-1 expression with response to first-line IFL regimen in mCRCs.. This prospective study analyzed patients diagnosed with mCRC between August 1st, 1998, and August 30th, 2003, at the Turku University Hospital, Finland. All patients received postoperative IFL regimen. Tumour expression of the MMR proteins, hMLH1 and hMSH2, and VEGF-1 expression were assessed by immunohistochemistry (IHC). Tumours with dMMR were those demonstrating loss of MMR protein expression, and tumours with high VEGF-1 expression were those showing moderate or strong cytoplasmic staining. The primary endpoint was the association between tumour hMLH1 or/and hMSH2-deficient and VEGF-1 expression; the relation between tumour MMR-status and IFL response rate was the secondary endpoint.. Of the 67 mCRCs patients, 29 (43%) were hMLH1 or/and hMSH2-deficient and 15 (22%) were pMMR mCRCs. At diagnosis, patients with hMLH1 or/and hMSH2-deficient tumours expressed lower levels of VEGF-1 compared to pMMR tumour patients (p=0.01). More than half (n=17, 59%) of those with dMMR were chemosensitive to first-line IFL regimen, while just one-fifth (n=3, 20%) of those with pMMR were chemosensitive to the IFL regimen (p=0.045).. Association between MMR-status and VEGF-1 expression predicts clinical outcome in mCRC patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Metastasis; Prospective Studies; Survival Analysis; Treatment Outcome; Vascular Endothelial Growth Factor A

The inhibition of the antiangiogenic pathway in association with chemotherapy significantly improved disease control and overall survival both in the upfront and in second line treatment of metastatic colorectal cancer patients. The VELOUR study had showed a significant improvement in overall survival with the addition of aflibercept, an antiangiogenic chimeric protein, to FOLFIRI (5-flourouracil, leucovorin, irinotecan) in patients who progressed after an oxaliplatin based chemotherapy (with or without bevacizumab) in first line treatment or within 6 months from the completion of adjuvant chemotherapy. Subgroup analyses from VELOUR trial show that the benefit of aflibercept is independent from previous exposure to bevacizumab in first line. We reported the case of a patient affected by metastatic colorectal adenocarcinoma RAS/ BRAF wild-type, with an initial liver-limited presentation. In this case we used a second line treatment with FOLFIRI aflibercept after a first-line oxaliplatin-based chemotherapy plus an anti-EGFR antibody.

Topics: Adenocarcinoma; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Oxaliplatin; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Randomized Controlled Trials as Topic; Topoisomerase Inhibitors

Topics: Antigens, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Histone Acetyltransferases; Humans; Hyaluronoglucosaminidase; Irinotecan; Leucovorin; Neoplasm Metastasis; Oxaliplatin; Pancreas; Pancreatic Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Neoplasm Metastasis; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Topoisomerase Inhibitors

Topics: Adenocarcinoma; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreas; Pancreatic Neoplasms

The present study investigated how well the results of integrative tumor-response assay (ITRA) compared to those of clinical response to chemotherapy in patients with metastatic colorectal cancer (CRC).. A total of 129 patients with metastatic CRC were prospectively enrolled. ITRA consisted of two sequential histoculture drug-response assays (HDRAs). First-stage HDRAs were performed using 5-fluorouracil with leucovorin and oxaliplatin (FX), or with irinotecan (FR). Second-stage HDRAs (ITRA) were performed for cells surviving after the first-stage HDRA, using FX, FR, and their combinations with bevacizumab and cetuximab.. Among 129 patients, 42 (32.6%) completed second-line chemotherapy, results that correlated with those of ITRA. The accuracy of ITRA for predicting response to second-line chemotherapy was 61.9% (26/42), with a sensitivity of 44.4% (8/18) and a specificity of 75% (18/24).. Despite its relatively low accuracy, ITRA might be a useful technique for predicting therapeutic efficacy and selecting for appropriate first-line and second-line anticancer regimens for patients.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Reproducibility of Results; Sensitivity and Specificity

FOLFIRINOX has increased efficacy but also toxicity. Despite various modified FOLFIRINOX regimens, how much reduction is acceptable remains unclear. This study aimed to find the optimal relative dose intensity (RDI, %) of FOLFIRINOX that preserves tumour responses in patients with advanced pancreatic cancer (PC).. We reviewed 201 patients with PC treated with first-line FOLFIRINOX during 2012-2015. We established a modified Hryniuk model (http://www.rdicalc.com) and defined cumulative RDI (cRDI, %). The optimal cRDI thresholds for response rate (RR) and disease control rate (DCR) were assessed using receiver operating characteristic (ROC) analysis. Relationships between cRDI and haematologic toxicities (neutropenia and febrile neutropenia [FN]) were also analysed according to use of granulocyte colony-stimulating factor (G-CSF).. Among 156 eligible patients, 133 (48 locally advanced PC and 85 metastatic PC) completed initial treatment plan prior to the first radiological evaluation (median 58 days; 71.8% cRDI). For optimal cRDI thresholds, ROC curves showed a 71.2% cRDI for RR (83.3% sensitivity, 64.7% specificity, and 0.746 area under the curve [AUC]) and a 55.3% cRDI for DCR (93.6% sensitivity, 62.5% specificity and 0.805 AUC). Among 96 patients who did not receive prophylactic G-CSF, cRDI ≥80.1% was a significant predictor for frequent FN (73.7% sensitivity, 72.7% specificity and 0.793 AUC). There was no correlation between cRDI and haematologic toxicities in patients receiving prophylactic G-CSF.. To preserve optimal RR and DCR in advanced PC, cRDI values for FOLFIRINOX >70% and >55%, respectively, are recommended. If cRDI is >80%, primary G-CSF prophylaxis is needed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Chemotherapy-Induced Febrile Neutropenia; Dose-Response Relationship, Drug; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

The occurrence of Chemotherapy-induced neutropenia (CIN) was reported to be a predictor of better survival in several cancers. The objective of our study is to evaluate the relationship between the timing of CIN and prognosis.. Between June 2012 and August 2014, 290 patients with confirmed metastatic colon cancer received at least one cycle of mFOLFOX6 as first-line chemotherapy were eligible for assessment as all patients group. Of the 232 received at least six cycles of mFOLFOX6 and survived 150 days after treatment were considered as landmark group. Timing of CIN was categorized into absence, early-onset and late-onset CIN groups. The end of cycle 3 was the cutoff to differentiate early-onset or late-onset. The correlation between timing of CIN with survival was analyzed by Kaplan-Meier method and Cox proportional hazards model.. In all patients group, the median survival of patients without neutropenia, early-onset and late-onset neutropenia were 6.7, 20.7 and 12.8 months (P < 0.001). The patients with early-onset and late-onset CIN had better prognosis than CIN absence by multivariate analysis. Findings were much the same for landmark group.. In conclusion, timing of CIN is an independent predictor of prognosis in metastatic colon cancer patients received mFOLFOX6, whereas an early-onset of CIN predicts longer survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Prognosis; Treatment Outcome

Few population studies have examined patterns of systemic therapy administration in metastatic pancreatic cancer (MPC) or the predictors associated with specific treatment choices.. We assessed 4,011 consecutive MPC patients who received chemotherapy between January 2005 and December 2015 at academic, private, and community-based oncology practices subscribing to a U.S.-wide chemotherapy order entry system capturing disease, patient, provider, and treatment data. Multivariate analyses of these prospectively recorded characteristics identified significant predictors of specific therapeutic choices.. Overall, 100 different regimens were used in first-line treatment of MPC. First-line gemcitabine monotherapy usage fell steadily from 72% in 2006 to 16% in 2015. This steep decline mirrored increases in first-line usage of both 5 fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine + nab-paclitaxel. Younger male patients were more likely to receive FOLFIRINOX as first-line treatment, whereas patients treated at community practices and by oncologists with lower MPC patient volume were more likely to receive gemcitabine plus nab-paclitaxel (all. This population-based study provides insight into treatment patterns of MPC in the U.S. Usage patterns varied greatly according to patient and provider characteristics.. This study examined real world metastatic pancreatic cancer treatment patterns in the United States with the goals of understanding changes in chemotherapy treatment frequencies over time and determining the individual predictors that underlie the chemotherapy choices oncologists make for their patients. Our data set is unique in that it captured not only patient-level data, but also oncologist-level data. It also captured data from private and community practices as well as academic centers. To our knowledge, this is the only data set that can give this degree of insight into oncologist decision making practices.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Decision Making; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; United States

The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab-based chemotherapy. Six single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5 and IRF7 were tested for the association with RR, PFS, and OS in KRAS-wild type mCRC patients. Patients treated with FOLFIRI + cetuximab or FOLFIRI + bevacizumab in the FIRE-3 trial served as a discovery set (FIRE3-Cet, n = 244) or a control set (FIRE3-Bev, n = 246), respectively. Patients treated with FOLFOX or SOX + cetuximab in the JACCRO-CC05/06 trial served as a validation set (JACCRO, n = 76). Genomic DNA isolated from tumor tissue samples was analyzed by PCR-based direct sequencing. In the discovery cohort, patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants (median 10.0 vs. 11.8 months, HR 1.39, p = 0.092). This preliminary association was confirmed in the validation cohort, and those with the G/G genotype showed a PFS benefit compared with others (univariate: 9.1 vs. 11.6 months, HR 2.04, p = 0.005, multivariate: HR 2.02, 95% CI: 1.14-3.55, p = 0.015). This association was not observed in the control cohort. Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab-based chemotherapy in mCRC patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Multicenter Studies as Topic; Neoplasm Metastasis; Polymorphism, Single Nucleotide; Predictive Value of Tests; Randomized Controlled Trials as Topic; RNA, Messenger; Toll-Like Receptor 7

The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting.. We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months.. Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCN<2.12 tumour, 63.6% had EGFR GCN⩾2.12 tumour; 50% had EGFR promoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, P<0.0001) and shorter overall survival (OS) (8 vs 13.6 months, P<0.0001). EGFR GCN<2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN<2.12 vs 39.3% for EGFR GCN⩾2.12 tumours, P=0.0009), shorter PFS (3.5 vs 6.5 months, P=0.0006) and shorter OS (8.5 vs 14.0 months, P<0.0001). Epidermal growth factor receptor-methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, P=0.0001), shorter PFS (3 vs 7.67 months, P<0.0001) and shorter OS (8 vs 17 months, P<0.0001). At multivariate analysis, EGFR GCN and EGFR promoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 and<0.0001) and OS (respectively P=0.0001 and<0.0001).. In our study, an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; DNA Methylation; DNA Mutational Analysis; DNA, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Gene Dosage; Genes, erbB-1; Genes, ras; Humans; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Promoter Regions, Genetic; Proto-Oncogene Proteins B-raf; Retreatment; Retrospective Studies; Survival Rate

Analysis of K- and N-RAS mutations is mandatory before planning treatment of metastatic colorectal cancer, because only RAS wild-type (WT) patients can benefit from treatment with anti-EGFR monoclonal antibodies (cetuximab and panitumumab).. Here we report the case of a 69-year-old male patient affected by metastatic sigmoid cancer. He underwent left hemicolectomy, and histology diagnosed a well-differentiated, pT4, node-positive adenocarcinoma; KRAS analysis performed with direct sequencing identified a mutation in exon 2 of the KRAS gene (GGT->GTT). After first-line chemotherapy with FOLFOX6 plus bevacizumab, the patient underwent surgical resection of residual liver metastases. Histology showed metastatic deposits from colic adenocarcinoma with extensive coagulative necrosis. Mutational analysis of the KRAS gene was also performed on liver metastases by pyrosequencing assay, and no mutation was identified. Due to the discordant results (GGT->GTT exon 2 KRAS mutation in the primary tumor, and KRAS-WT in the liver metastases), mutational analysis on liver metastasis was repeated using next-generation sequencing and enriching the sample in tumor cells by manual microdissection; the same type of mutation of the primary tumor (GGT->GTT exon 2 KRAS gene) was confirmed.. Accurate tissue sampling and adequately sensitive assays are essential to correctly identify colorectal cancer patients who can be treated with an anti-EGFR monoclonal antibody.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Exons; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras); ras Proteins

Overexpression of HER2 protein and amplification of the

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Combined Modality Therapy; Duodenal Neoplasms; Endoscopy, Digestive System; Female; Fluorouracil; Gene Amplification; Humans; In Situ Hybridization, Fluorescence; Leucovorin; Magnetic Resonance Imaging; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Receptor, ErbB-2; Trastuzumab; Treatment Outcome

The economic burden of metastatic pancreatic cancer (mPC) is substantial while treatment options are limited. Little is known about the treatment patterns and healthcare costs among mPC patients who initiated first-line gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-P + G) and FOLFIRINOX.. The MarketScan® claims databases were used to identify adults with ≥2 claims for pancreatic cancer, 1 claim for a secondary malignancy, completed ≥1 cycle of nab-P + G or FOLFIRINOX during 4/1/2013 and 3/31/2015, and had continuous plan enrollment for ≥6 months pre- and 3 months after the first-line treatment. Duration of therapy, per patient per month (PPPM) costs of total healthcare, mPC-related treatment, and supportive care were measured during first-line therapy.. 550 mPC patients met selection criteria (nab-P + G, n = 294; FOLFIRINOX, n = 256). There was no difference in duration of therapy (p = 0.60) between nab-P + G and FOLFIRINOX. Compared with FOLFIRINOX, patients with nab-P + G had higher chemotherapy drug costs but lower treatment administration costs and supportive care costs (all p < 0.01).. Patients treated with nab-P + G (vs FOLFIRINOX) had similar treatment duration but lower costs of outpatient prescriptions, treatment administration and supportive care. Lower supportive care costs in the nab-P + G cohort were mainly driven by lower utilization of pegfilgrastim and anti-emetics.

Topics: Aged; Albumins; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Cost of Illness; Deoxycytidine; Drug Costs; Female; Filgrastim; Fluorouracil; Gemcitabine; Granulocyte Colony-Stimulating Factor; Health Care Costs; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Polyethylene Glycols; Recombinant Proteins; Retrospective Studies; Time Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Medical Oncology; Nanostructures; Neoplasm Metastasis; Pancreatic Neoplasms

Given Saskatchewan's size and low population density outside of city centres, many rural and remote residents have issues accessing regional oncology services. We performed a study to determine whether travel distance to cancer treatment centres affects first-line treatment accessibility and survival in patients with metastatic colorectal adenocarcinoma.. Retrospective chart review of patients with stage IV metastatic colorectal adenocarcinoma collected by the Saskatchewan Cancer Agency registry between June 1, 2009, and June 30, 2013. Patients were categorized as living within 100 km of or more than 100 km from the nearest cancer treatment centre offering bevacizumab plus first-line chemotherapy. Main outcome measures were differences in first-line treatment accessibility and overall survival estimates (calculated via the Kaplan-Meier method) between cohorts.. Of the 252 included patients, 91 (36.1%) resided more than 100 km from a cancer treatment centre. Accessibility of standard single-agent and combination chemotherapy in the first-line setting, when not prescribed in conjunction with bevacizumab, was comparable between cohorts. Patients living within 100 km of a treatment centre and those living more than 100 km from a treatment centre had comparable access to bevacizumab in conjunction with first-line chemotherapy (57 [62.6%] v. 116 [72.0%] patients;. Neither access to bevacizumab treatment nor survival times for metastatic colorectal adenocarcinoma were significantly different between the cohorts. This suggests that health care providers in Saskatchewan may be doing well in arranging timely access to advanced oncology centres. Future studies with a larger sample, different tumour types or changes to the definition of remoteness are indicated.. Compte tenu de la taille de la Saskatchewan et de la faible densité de sa population hors des centres urbains, beaucoup de personnes en régions rurales et éloignées ont de la difficulté à obtenir des services d’oncologie régionaux. Nous avons mené une étude pour déterminer si la distance à parcourir pour se rendre aux centres de traitement du cancer a des répercussions sur l’accès aux traitements de première intention et sur la survie des patients atteints d’adénocarcinome colorectal métastasique.. Nous avons procédé à un examen rétrospectif des dossiers du registre de la Saskatchewan Cancer Agency portant sur les patients atteints d’adénocarcinome colorectal métastasique de stade IV, pour la période du 1. Sur les 252 patients de l’étude, 91 (36,1 %) habitaient à plus de 100 km d’un centre de traitement du cancer. L’accès à une monothérapie standard et à une chimiothérapie combinée en première intention, lorsque non prescrite en même temps que le bévacizumab, était comparable entre les cohortes. Les patients vivant à moins de 100 km d’un centre de traitement et ceux vivant à plus de 100 km d’un centre de traitement avaient un accès comparable au bévacizumab associé à la chimiothérapie de première intention (57 [62,6 %] c. 116 [72,0 %] patients;. Il n’y avait aucune différence sur le plan statistique entre les cohortes pour ce qui est de l’accès au traitement de bévacizumab et de la durée de survie pour l’adénocarcinome colorectal métastasique. Ces résultats suggèrent que les professionnels de la santé de la Saskatchewan réussissent bien à prévoir l’accès rapide aux centres de traitement avancé en oncologie. D’autres études sont nécessaires au moyen d’un échantillon plus important, sur d’autres types de tumeurs ou en modifiant la définition de l’éloignement.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Health Services Accessibility; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Registries; Retrospective Studies; Saskatchewan; Survival Rate; Travel

Readministration of anti-epidermal growth factor receptor (EGFR) antibody for metastatic colorectal cancer (mCRC) after disease progression remains to be determined.. Readministration of anti-EGFR antibody in mCRC patients previously refractory to anti-EGFR antibody was prospectively observed.. A total of thirteen patients with a median age of 60-years old and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled. The median number of previous chemotherapies was 3 (range 2-5). Prior anti-EGFR antibody in combination with cytotoxic drugs was administered in 12 patients. Anti-EGFR antibody readministration regimens were cetuximab/panitumumab plus capecitabine/S-1 (seven patients), panitumumab plus FOLFOX (three patients), cetuximab plus irinotecan (two patients), and panitumumab monotherapy (one patient). Seven patients showed stable disease following readministration and six patients showed progressive disease. The median overall survival (OS) following readministration was 228 days and the median PFS was 102 days. Patients with intervals longer than 90 days between anti-EGFR therapies exhibited more favorable survival than those with intervals shorter than 90 days. Switching of anti-EGFR antibody between treatments was observed to contribute survival.. Anti-EGFR antibody readministration could show a modest survival benefit in mCRC patients, with the length of therapy interval and switching of antibody being important contributory factors.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Retreatment; Retrospective Studies; Survival Analysis; Treatment Outcome

FOLFIRINOX is a first-line treatment option for patients with metastatic pancreatic cancer (MPC) and is associated with improved survival yet significantly more toxicities than standard gemcitabine. Our aim was to determine the proportion of patients with MPC who would be eligible for FOLFIRINOX based upon the pivotal ACCORD study criteria.. Patients with confirmed MPC at the time of referral to the BC Cancer Agency between 2004 and 2007 were identified from the Gastrointestinal Cancers Outcomes Unit Database (GICOU). Proportion of patients that met the ACCORD study eligibility criteria was determined by chart review. Criteria for FOLFIRINOX exclusion were assessed using descriptive statistics.. A total of 100 consecutive patients with complete chart records and MPC were identified. Fifty-two (52%) were male and the median age was 68 years (range, 42 to 98 y). The most common sites of metastases were liver (63%) and peritoneum (22%). Only 26 patients fulfilled the ACCORD study eligibility criteria. The most common reasons for FOLIFIRINOX exclusion per ACCORD were poor Eastern Cooperative Oncology Group score of ≥2 (64%), age of 76 years or greater (22%), elevated bilirubin (22%), and inadequate renal function (6%).. Despite the proven survival benefit of FOLFIRINOX, only approximately one quarter of patients in the real-world setting with MPC would have been considered eligible for such therapy based upon the ACCORD eligibility criteria. Careful patient selection and more tolerable therapies are required.

Topics: Activities of Daily Living; Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; British Columbia; Camptothecin; Eligibility Determination; Female; Fluorouracil; Humans; Hyperbilirubinemia; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Peritoneal Neoplasms; Renal Insufficiency; Retrospective Studies

We analyzed the results of previously treated patients with metastatic colorectal cancer (mCRC) who received regorafenib plus FOLFIRI with the irinotecan dose escalation on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping. Thirteen patients with previously treated mCRC were subjected to UGT1A1 genotyping between October 2013 and June 2015 and were administered regorafenib plus FOLFIRI with irinotecan dose escalation. Patients with UGT1A1*1/*1 and *1/*28 genotypes were administered 180 mg/m2 of irinotecan, whereas those with the UGT1A1*28/*28 genotype were administered 120 mg/m2 of irinotecan. For all patients, the irinotecan dose was increased by 30 mg/m2 every two cycles until grade ≥3 adverse events or severe adverse events developed, following which the dose was reverted to and maintained at the previously tolerated level. The oral regorafenib dose was adjusted to 120 mg/day daily. The median follow-up period was 10.0 months (1.0-21.0 months). The disease control rate was 69.2%, whereas the median progression-free survival and overall survival were 9.5 and 13.0 months, respectively. Our findings indicate that regorafenib plus FOLFIRI with irinotecan dose escalation based on UGT1A1 genotyping in previously treated patients with mCRC and with UGT1A1*1/*1 and UGT1A1*1/*28 genotypes is clinically effective and yields improved oncological outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Phenylurea Compounds; Pyridines; Retreatment; Treatment Outcome

Patients with locally advanced rectal cancer (LARC) receiving neoadjuvant chemoradiation (nCRT) can have a complete pathologic response (pCR), and are given postoperative adjuvant chemotherapy (ACT).. A prospectively maintained outcomes database was queried for patients who had pCR to nCRT for LARC from 2000 to 2012. Local recurrence and survival were analyzed according to whether patients received ACT.. We identified 139 patients and excluded 9 due to lack of follow-up. Mean age was 58.9 ± 11.8 years. 83 patients (63.8%) did not receive ACT (Group A) and 47 (36.2%) did (Group B). Mean follow-up was 5.7 ± 3 and 5.6 ± 3.5 years for Groups A and B respectively (p = 0.51). Groups were comparable in age, gender, tumor differentiation, and clinical staging. There were no differences in oncological outcomes.. Avoiding routine use of ACT in patients with a pCR may be considered. Further justification of this approach warrants prospective randomized studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prospective Studies; Rectal Neoplasms

Adding cetuximab to FOLFIRI (5-fluorouracil, leucovorin, irinotecan) significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with KRAS or RAS (KRAS/NRAS, exons 2-4) wild-type (wt) metastatic colorectal cancer (mCRC) in the first-line CRYSTAL study. The present exploratory and descriptive retrospective analysis assessed the quality of life (QoL) of CRYSTAL study patients with RAS wt mCRC-the labeled indication for cetuximab in many countries.. Patient QoL was investigated using the European Organisation for Research and Treatment of Cancer QoL questionnaire core-30 (EORTC QLQ-C30). QoL assessments were performed at baseline, after every 8 weeks of treatment, and at the final tumor assessment. RAS wt patients were considered evaluable for QoL if they had provided ≥ 1 evaluable EORTC QLQ-C30.. Of the 367 patients with RAS wt tumors, 351 were evaluable for QoL. Global health status (GHS)/QoL and the time to worsening of Eastern Cooperative Oncology Group performance status were similar between the treatment groups. However, the analysis was complicated by a large decrease in the number of evaluable patients in the FOLFIRI arm between weeks 32 and 40. The individual dimensions of interest in mCRC (eg, social functioning, fatigue, nausea/vomiting, pain, appetite loss, constipation, diarrhea, and functional difficulties) were also similar between the treatment arms. Changes in GHS/QoL and social functioning from baseline to week 8 were similar, irrespective of whether patients experienced early skin reactions.. The findings of the present descriptive retrospective analysis suggest that adding cetuximab to first-line FOLFIRI improves PFS, OS, and ORR without negatively affecting the QoL of CRYSTAL study patients with RAS wt mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins p21(ras); Quality of Life; ras Proteins; Retrospective Studies; Survival Rate; Young Adult

Predictive biomarkers of efficacy and toxicity of bevacizumab have not yet been validated. This study assessed the influence of IL-8, eNOS and VEGF-A polymorphisms in RAS mutated metastatic colorectal cancer patients receiving bevacizumab-based chemotherapy.. 120 patients treated with first-line combination FOLFOX6 plus bevacizumab were included. A historical cohort of 112 RAS mutated colorectal cancer patients treated with FOLFOX6 alone served as control group. The following SNPs were analyzed: IL-8 c.-251T>A; eNOS c.-786T>C and c.-894G>T; VEGF-A c.936C>T, c.958T>C, c.1154A>G and c.2578C>A. Correlation of SNPs, baseline IL-8 serum levels and bevacizumab-efficacy was done.. In the bevacizumab group, carriers of the IL-8 alleles c.-251TA+AA showed a shorter PFS (P=0.002) and OS (P=0.03) compared to TT alleles. Patients with pre-treatment IL-8 < 18.25 pg/ml showed significantly longer median PFS and OS (PFS: 10.9 vs 7.6 months, P=0.005; OS: 30.7 vs 18.2 months, P<0.001) compared to patients with IL-8 higher levels (>18,25 pg/ml). IL-8 c.-251TA+AA carriers had significantly higher IL-8 levels (P<0.0001). Multivariate analysis confirmed association of IL-8 polymorphism with PFS, and of IL-8 baseline levels with both PFS and OS. IL-8 SNP did not affect the outcome in the control group. The eNOS polymorphism c.-894G>T was found associated with higher severe toxicity (P=0.0002) in patients carrying the c.-894TT genotype.. Although our data need prospective validation, IL-8 and eNOS SNPs may be have a role as predictive biomarkers for bevacizumab efficacy and toxicity.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cohort Studies; Colorectal Neoplasms; Female; Fluorouracil; Humans; Interleukin-8; Leucovorin; Male; Mutation; Neoplasm Metastasis; Nitric Oxide Synthase Type III; Organoplatinum Compounds; Polymorphism, Single Nucleotide; ras Proteins; Treatment Outcome

Irinotecan-based chemotherapy is a standard backbone of therapy in patients with metastatic colorectal cancer (CRC) or gastric cancer (GC). However, there is still a paucity of information concerning the efficacy and safety of irinotecan-based regimens in elderly patients.. Using the patient cohort (. Despite lower relative dose intensity in elderly patients, progression-free survival and overall survival were similar between elderly (age ≥70 years) and nonelderly (<70 years) patients in the CRC cohort (hazard ratio [HR], 1.117; 95% confidence interval [CI], 0.927-1.345;. The efficacy of the FOLFIRI regimen was similar between elderly and nonelderly patients in both the CRC and the GC cohorts. However, special attention should be paid to elderly patients because of increased risk for febrile neutropenia and asthenia.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Glucuronosyltransferase; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Nausea; Neoplasm Metastasis; Stomach Neoplasms; Treatment Outcome; Vomiting

Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy.. We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed.. We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P=0.003), but not to FOLFOX (P=0.911) and FOLFIRI + Bevacizumab (P=0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months).. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Survival Rate; Transcriptome; Treatment Outcome

Hypermethylation of the CpG island of p16(INK4a) occurs in a significant proportion of colorectal cancer (CRC). We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), and cetuximab.. Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, and hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype (CIMP) markers including p16 and clinical outcome.. Hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6%) and showed significant association with KRAS mutation (Fisher exact, p=0.01) and CIMP positivity (Fisher exact, p=0.002). Patients with p16-unmethylated tumors had significantly longer time to progression (TTP; median, 9.0 months vs. 3.5 months; log-rank, p=0.001) and overall survival (median, 44.9 months vs. 16.4 months; log-rank, p=0.008) than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy (n=6) had markedly shortened TTP (median, 2.8 months) compared to those with either KRAS or p16 aberrancy (n=11; median, 8.6 months; p=0.021) or those with neither (n=32; median, 9.0 months; p < 0.0001). In multivariate analysis, KRAS mutation and p16 methylation showed independent association with shorter TTP (KRAS mutation: hazard ratio [HR], 3.21; p=0.017; p16 methylation: HR, 2.97; p=0.027).. Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.

Topics: Adult; Aged; Cetuximab; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; Female; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Prognosis; Proto-Oncogene Proteins p21(ras); Treatment Outcome

The aim of this study was to compare the efficacy and hematologic toxicity of cetuximab combined with various types of chemotherapy regimens in patients with KRAS wild-type metastatic colorectal cancer (mCRC).. The response rate, progression-free survival (PFS) and overall survival of the patients were analyzed.. In total, 45 patients were included in the study. The overall response rate for the combination of cetuximab and FOLFOX, FOLFIRI and CAPOX was 20, 46 and 30%, respectively, but the differences were not statistically significant. The median PFS for the three groups were 8, 6 and 3.5 months, respectively, but again these differences were not significant. All-grade leukopenia and anemia for the cetuximab plus FOLFOX group were significantly higher than for the other chemotherapy regimens.. Our findings suggest that the combination of cetuximab and the three standard chemotherapy regimens resulted in the same outcomes in our patient population of mCRC, with higher hematologic toxicities among the FOLFOX subgroup.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Proto-Oncogene Proteins p21(ras); Retrospective Studies; Survival Rate

As a surrogate marker of systemic inflammation, the lymphocyte-to-monocyte ratio (LMR) is an independent prognostic factor for various malignancies. This study investigated the prognostic significance of the pre-chemotherapy LMR in patients with previously untreated metastatic colorectal cancer (mCRC) receiving chemotherapy.. The present study included newly diagnosed mCRC patients treated between January 2005 and December 2013 with FOLFOX chemotherapy, specifically oxaliplatin 180 mg/m(2) on day 1, with leucovorin 400 mg/m(2) administered as a 2-hour infusion before the administration of 5-fluorouracil 400 mg/m(2) as an intravenous bolus injection, and 5-fluorouracil 2400 mg/m(2) as a 46-h infusion immediately after 5-fluorouracil bolus injection. The LMR was calculated as the absolute count of lymphocytes divided by the absolute count of monocytes. COX proportional hazards analysis was performed to evaluate the association of LMR with survival outcomes.. A total of 488 patients were included. Patients with high pre-chemotherapy LMR experienced significant improvements in progression-free survival (PFS, 9.2 vs. 7.6 months, P < 0.001) and overall survival (OS, 19.4 vs. 16.6 months, P < 0.001) compared with patients with low pre-chemotherapy LMR. Subsequent COX multivariate analysis showed that high pre-chemotherapy LMR (≥3.11) was an independent favorable prognostic factor for PFS and OS. Additionally, patients whose LMR remained high (high-high subgroup), increased (low-high subgroup), or decreased (high-low subgroup) following chemotherapy showed better results in terms of PFS and OS than patients whose LMR remained low (low-low subgroup) after chemotherapy.. For patients with previously untreated mCRC receiving FOLFOX chemotherapy, an elevated pre-chemotherapy LMR is an independent favorable prognostic factor for PFS and OS, and changes in the LMR before and after chemotherapy seem to predict the benefit of chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Lymphocyte Count; Male; Middle Aged; Monocytes; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Survival Analysis; Treatment Outcome

This study assessed second-line continued use of cetuximab for treatment of unresectable metastatic colorectal cancer (mCRC) after disease progression during first-line cetuximab-based therapy. Consecutive patients with wild-type KRAS exon 2 and unresectable mCRC were retrospectively enrolled after disease progression during first-line cetuximab-based chemotherapy. Second-line continued cetuximab plus changed chemotherapy (cetuximab continuation group, n = 102) was compared with changed chemotherapy only (chemotherapy only group, n = 96) with respect to treatment efficacy and safety endpoints. NRAS and other KRAS genotypes were also detected as a post hoc analysis. The cetuximab continuation group showed better progression-free survival (median, 6.3 vs. 4.5 months, P = 0.004), overall survival (median, 17.3 vs. 14.0 months, P < 0.001) and disease control rate (70.6% vs. 53.1%, P = 0.011), and a potentially better overall response rate (18.6% vs. 9.4%, P = 0.062) than the chemotherapy only group. These benefits were seen mainly in patients with all RAS wild-type and exhibiting first-line early tumor shrinkage (ETS). For patients with other RAS mutations or who did not achieve first-line ETS, there was no difference between the two groups. These findings suggest that for patients with all RAS wild-type and unresectable mCRC who had disease progression during first-line cetuximab-based treatment, second-line continued cetuximab is effective. Moreover, ETS during first-line cetuximab-based treatment may be predictive of the efficacy of second-line continued cetuximab.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Cohort Studies; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras); Retrospective Studies

Over the past decade, oncology therapies have trended toward orally administered regimens, and there has been growing attention on evaluation of factors that affect adherence. There has not been a rigorous investigation of factors associated with adherence to intravenous (i.v.) and oral anticancer drugs in the setting of metastatic colorectal cancer (mCRC).. To (a) assess potential patient-specific factors related to adherence to mCRC chemotherapy regimens and (b) compare adherence with IV versus oral dosage forms.. A retrospective analysis was performed using the Optum Oncology Management claims database. Patients aged 18 years and older diagnosed with mCRC between July 1, 2004, and December 31, 2010, who were insured by a commercial health plan were included in the study. Adherence to i.v. and oral chemotherapy regimens was assessed using the National Comprehensive Cancer Network (NCCN) guidelines as the standard for expected cycle/regimen duration. The most commonly prescribed chemotherapy regimens were assessed. Adherence was evaluated using the medication possession ratio (MPR), calculated as the number of days a patient was covered by their chemotherapy regimen, according to NCCN guidelines, divided by the number of days elapsed from the first to the last infusion of that regimen. For most analyses, the MPR was considered a continuous variable that could take on values between 0 and 1. In other analyses, a dichotomous categorical variable designated if the MPR was at least 0.8 versus less than 0.8. The Wilcoxon rank sum, Kruskal-Wallis, and Student's t-test were used to detect differences in continuous measures between patients receiving oral capecitabine therapy versus i.v. chemotherapy. The chi square test (X(2) test) or Fisher's exact test was used to assess differences in the dichotomous MPR variable. Generalized estimating equation (GEE) models were used for regimen-level analyses to account for correlated responses within individuals.. A total of 6,780 patients were included in the analysis, virtually all (98%) with commercial insurance coverage and the remaining (2%) with Medicare Advantage. Patients with mCRC received 17,095 regimens of chemotherapy, including 2,252 regimens of oral capecitabine. Of the 17,095 regimens, 6,780 (40%) were first-line regimens (i.e., the first time mCRC was treated for a given patient). The most common chemotherapy regimen, regardless of line of therapy, was FOLFOX (2,991 regimens, 17.5% of all regimens used). FOLFOX-based therapies with or without bevacizumab were the most common regimens for first- and second-line chemotherapy, while oral capecitabine treatment was the most commonly prescribed regimen for patients in third- or fourth-line therapy. Overall, medication adherence across all regimens was relatively high, with a mean MPR of 0.87 (SD = 0.17). Evaluation of the distribution of i.v. and oral capecitabine regimens revealed that 28% of all regimens were associated with an MPR of less than 0.8. The average MPR was clinically similar, but statistically higher for i.v. chemotherapy regimens (0.881) compared with oral capecitabine regimens (0.799; P < 0.0001). In the multivariable GEE model, lung or liver metastases were associated with a higher MPR, while lower Charlson Comorbidity Index and oral anticancer therapy were associated with lower MPR. Furthermore, as line of therapy increased, the difference in MPR between patients receiving oral capecitabine and i.v. chemotherapy increased.. This analysis determined that adherence with i.v. chemotherapy regimens was clinically similar, but statistically higher, compared to oral capecitabine therapy. The difference in adherence rates between the 2 routes of administration increased as the line of anticancer regimen increased. These results suggest that there should be an increased focus on improving adherence rates in patients receiving oral capecitabine.

Topics: Administration, Intravenous; Administration, Oral; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Medicare Part C; Medication Adherence; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies; United States

FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty-seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19-9.81) and 12 months (95% CI 9.75-14.25), respectively. Response rate was 38.6%, while disease-control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42-3.59) and neutrophil-lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38-4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good-risk (0 factors, 38 pts), intermediate-risk (1 factor, 49 pts) and poor-risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Female; Fluorouracil; Humans; Leucovorin; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Neutrophils; Organoplatinum Compounds; Pancreatic Neoplasms; Prognosis; Survival Analysis; Treatment Outcome

The effect of individual dose adjustment of 5-fluorouracil (5-FU) based on pharmacokinetic monitoring on the outcome of FOLFOX for metastatic colorectal cancer was analyzed retrospectively.. Twenty patients with metastatic colorectal cancer underwent FOLFOX chemotherapy from January 2005 to December 2013 at the Niitsu Medical Center Hospital. The sample group included 11 patients in whom 5-FU doses were adjusted individually based on pharmacokinetic monitoring according to an algorithm to maintain the area under the curve (AUC) in the range of 20-25 mg·h/L (Group A) and 9 patients in whom 5-FU doses were adjusted conventionally based on body surface area (Group B).. The objective response rate was 63% and 33% in Group A and Group B, respectively (p=0.174). The median overall survival was 34 months and 14 months in Group A and Group B, respectively (p=0.036). There were 4 cases of Grade 3 toxicity (2 in Group A, 2 in Group B; p=0.636) and no cases of Grade 4 toxicity or treatment-related death.. Pharmacokinetically guided dose adjustment of 5-FU may improve the outcome of FOLFOX for metastatic colorectal cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Rectal Neoplasms; Recurrence; Retrospective Studies

This study was aimed to assess the feasibility and short-term outcomes of adjuvant systemic chemotherapy with either S-1/oxaliplatin (SOX) or mFOLFOX6 (FOLFOX)after curative resection of distant metastases from colorectal cancer. We retrospectively examined 16 patients who underwent R0 resection of colorectal metastases, including the liver (n=6), lung (n=5), lymph node (n=3), and peritoneum (n=2), followed by chemotherapy with SOX (n=7) or FOLFOX (n=9) until disease progression. The mean recurrence-free survival was 13.2 months in the SOX group and 16.9 months in the FOLFOX group. The mean overall survival was 17.9 and 22.9 months, respectively. The number of given courses were 6.5 and 11.0, respectively. Although sensory neuropathy was observed in 38% of the patients, relative dose intensity was higher than 80%. Adjuvant chemotherapy with SOX or FOLFOX was feasible and effective. Further randomized prospective trials are warranted to confirm these results.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Rectal Neoplasms; Recurrence; Retrospective Studies; Tegafur

To evaluate the safety and efficacy of the combination therapy of fluorouracil, leucovorin and irinotecan (FOLFIRI) and aflibercept in Asian patients with metastatic colorectal cancer (mCRC), who had progressed after oxaliplatin-based chemotherapy.. This is a retrospective analysis of 19 mCRC patients who received FOLFIRI and aflibercept (4 mg/kg intravenously) every 2 weeks via a Named Patient Program (supported by Sanofi Aventis) in Singapore. Treatment was administered until disease progression or unacceptable toxicities. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Efficacy and toxicities were summarized using descriptive statistics. Statistical analysis was performed using STATA 12.0 software.. The majority (84%) of the patients were of chinese ethnicity. The median age was 59 years, with 63.2% of the patients having an Eastern Cooperative Oncology Group status of 1. Four patients (21.1%) achieved partial response and 8 patients (42.1%) achieved stable disease. After a median follow-up of 9.6 months [95% confidence interval (CI), 2.2-13.1 months], the median OS was 11.6 months (95% CI, 6.1 to not-estimable), and median PFS was 4.1 months (95% CI, 2.2-5.9). Majority of the toxicities were grade 1-2, and include leucopenia (84.2%), anemia (73.7%), liver enzyme elevation (68.4%) and fatigue (68.4%). The most frequently reported grade 3 toxicities were neutropenia and neutropenic complications (both 15.8%). All adverse events resolved with supportive management.. The clinical benefit and safety profile of the combination of FOLFIRI/aflibercept in Asian patients with mCRC are consistent with that of Western population. FOLFIRI/aflibercept may be an appropriate therapeutic option in Asian patients with mCRC previously treated with an oxaliplatin-based regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retrospective Studies

Effectiveness of bevacizumab for metastatic colorectal cancer in elderly patients has been investigated in observational studies, mainly associated with oxaliplatin-based regimens. Here, using the ETNA cohort in which the majority of patients received bevacizumab+FOLFIRI, the effectiveness of this combination in elderly patients is explored.. Patients initiating first-line therapy with bevacizumab between January 2006 and December 2007 were identified in 28 French centres and followed for 24months. Vital status was collected over 36months. In the present analysis those who received FOLFIRI were retained (85% of those included), and patients were stratified by age (<70/≥70years). The Kaplan-Meier method estimated progression-free survival (PFS) and overall survival (OS), and Cox models were used to assess the independent effect of age on survival outcomes.. Among the 351 patients who received bevacizumab+FOLFIRI, 33.9% were aged ≥70years, 66.1% <70years. Respectively 15.1% and 9.5% of patients had ECOG-PS ≥2; 49.6% and 40.1% used 'stop-and-go' treatment scheduling; and 56.3% and 44.4% experienced grade 3/4 adverse events. Overall response rate was 58.8% and 62.5%. Median [95% confidence interval, CI] OS was respectively 24.1 [20.4; 26.2] and 28.5 [25.0; 31.0] months; age≥70years and ECOG-PS≥2 were significantly associated with death. Median PFS [95% CI] was respectively 10.9 [9.4; 12.6] and 9.8 [9.2; 11.2] months; hepatic metastases was associated with progression, and age ≥70years was associated with progression after 14months of follow-up but not before.. The present study adds to the literature on the safe and beneficial effect of bevacizumab in the elderly receiving FOLFIRI regimen.

Topics: Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cohort Studies; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Survival Rate

Currently, there is no standard salvage regimen after the failure of cisplatin-based chemotherapy for advanced urothelial carcinoma. The combination of epidermal growth factor receptor inhibitor with fluorouracil, leucovorin, and irinotecan was originally designed for the treatment of metastatic colorectal cancer. Until now, there have been no reports using this combination therapy in treating advanced upper tract urothelial carcinoma. To the best of our knowledge, this is the first report showing this possible treatment regimen for advanced upper tract urothelial carcinoma.. We report the case of a 90-year-old Chinese woman who was diagnosed with metastatic colorectal cancer and urothelial carcinoma of the bladder, ureter, and renal pelvis. The upper tract urothelial carcinoma was well controlled by the chemotherapy regimen for metastatic colorectal cancer. Considering her age, we used only laser ablation for the treatment of her urothelial carcinoma in combination with intravesical mitomycin C chemotherapy. Follow-up cystoscopy and ureterorenoscopy showed an unexpected regression of the upper tract urothelial tumor. Contrast-enhanced computed tomography also demonstrated the same results.. This novel regimen for the treatment of upper tract urothelial carcinoma may merit further investigation or evaluation in clinical trials.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Neoplasms, Second Primary; Urologic Neoplasms

Several chemotherapy regimens using bevacizumab have been developed. Our goal was to investigate regimens that have demonstrated significant clinical activity in patients with metastatic colorectal cancer (mCRC).. Six hundred and sixty six patients with mCRC who received first-line chemotherapy combination with bevacizumab were studied. Fluoropyrimidine (F) plus irinotecan (I)-based (FI-bev), F plus oxaliplatin (O)-based (FO-bev), and F-based (F-bev) treatment regimens were compared with respect to progression-free survival (PFS) and overall survival (OS).. The median PFS of FI-bev (n = 414) was 10.9 months (95 % CI 10-11.8), of FO-bev (n = 211) was 9.4 months (95 % CI 8.3-10.4), and of F-bev (n = 41) was 9.5 months (95 % CI 5.9-13.1) (p = 0.089). The median OS of FI-bev was 26.3 months (95 % CI 21.7-30.9), of FO-bev was 27 months (95 % CI 24.3-29.7), and of F-bev was 23.3 months (95 % CI 12.7-33.9) (p = 0.102). In KRAS wild-type patients, the median PFS of FI-bev group was significantly longer than FO-bev group (10.5 vs. 9.1 months, p = 0.006). The FI-bev group had better OS than FO-bev group with borderline significance (p = 0.058). The FI-bev group had significantly longer OS than F-bev group. Patients who underwent metastasectomy or those with Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 had longer PFS and OS independent of the type of chemotherapy regimen.. FI-bev may be the preferred frontline regimen for patients with KRAS wild-type mCRC. Metastasectomy and performance score were the strongest positive predictors of OS and PFS regardless of backbone chemotherapy regimen.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Treatment Outcome; Turkey

The purpose of this study was to evaluate the clinical significance of single-nucleotide polymorphisms in TLR1, TLR2, TLR6, and TAK1 in patients with metastatic colorectal cancer (mCRC). We genotyped 9 SNPs of TLR1, TLR2, TLR6, and TAK1 in mCRC patients treated with first-line FOLFIRI (combination therapy of irinotecan, 5-fluorouracil, and folinic acid) plus bevacizumab, using a discovery cohort (TRIBE trial, n = 228) and a validation cohort (FIRE-3 trial, n = 297), and analyzed for the association with response rate (RR), progression-free survival (PFS), and overall survival (OS). There was a significant association of TLR1 rs5743618 (T1805G) with the clinical outcome. In the TRIBE cohort, a homozygous wild-type genotype (T/T) associated with a significantly lower RR compared with variant T/G and G/G genotypes (43% vs. 62%, P = 0.025), and this observation was validated in the FIRE-3 cohort (46% vs. 65%, P = 0.021). In addition, those patients with the T/T genotype had significantly worse PFS (median, 8.2 vs. 10.5 months; HR, 1.57; 95% CI, 1.09-2.28, P = 0.014) and OS (median: 19.9 vs. 27.9 months; HR, 1.63; 95% CI, 1.14-2.35, P = 0.007), compared with those with other genotypes in the TRIBE cohort. These differences remained statistically significant in multivariate analysis. Our data suggest that TLR1 rs5743618 could serve as a predictor of clinical response to FOLFIRI plus bevacizumab in patients with mCRC. Mol Cancer Ther; 15(7); 1740-5. ©2016 AACR.

Topics: Aged; Aged, 80 and over; Alleles; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Genes, ras; Genotype; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Polymorphism, Single Nucleotide; Retreatment; Toll-Like Receptor 1; Treatment Outcome

Retrospective studies have found that early tumor shrinkage (ETS) and depth of response (DpR) are associated with favorable outcomes in patients with metastatic colorectal cancer (mCRC); however, few prospective studies have evaluated ETS and DpR.. We performed a phase II study of FOLFOX plus cetuximab as first-line treatment in Japanese patients with KRAS wild-type mCRC. The primary endpoint was response rate (RR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), chronological tumor shrinkage (evaluated every 8 weeks), and safety. The association of ETS and DpR with survival time was analyzed using Spearman's rank correlation coefficient.. In 54 participants, the RR, median PFS, and OS were 66.7 % (95 % CI, 53.4-77.8 %), 11.1 months, and 33.9 months, respectively. There was no unexpected toxicity. Forty (80 %) of 50 assessable patients had ETS, which was associated with prolonged PFS and OS (11.3 vs. 3.7 months, HR 0.26, p = 0.0003; 42.8 vs. 9.0 months, HR 0.40, p = 0.0279, respectively). Median DpR was 56.3 %. The DpR correlated with OS (r. Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy (UMIN000004197).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies; Treatment Outcome; Young Adult

The treatment of metastatic colorectal cancer (mCRC) has changed substantially in the last 2 decades, but to the authors' knowledge, the effect of age and comorbidities on chemotherapy use has not been well studied to date.. Patients with mCRC who were being treated with 5-fluorouracil (5-FU)-based chemotherapy between January 1995 to December 2009 were studied using the LifeLink Health Plan Claims Database. The cohort was divided into older (aged >70 years) and younger (aged ≤70 years) patients. The Charlson Comorbidity Index (CCI) was used to assess comorbidity burden. The Wilcoxon and chi-square tests were used in univariate and logistic regression in multivariate analyses.. A total of 16,087 patients were identified, with 24% of the patients who were receiving chemotherapy being aged >70 years. The percentage of patients with a CCI >1 receiving chemotherapy increased over time (14% in 1996 vs 40% after 2004; P<.05). Older patients were less likely to receive treatment with >2 agents compared with younger patients (15% vs.22% and 11% vs.16%, respectively, in 2003 and 2009; P<.001). After approval by the US Food and Drug Administration in 1998, the use of irinotecan was lower in older compared with younger patients, a difference that resolved by 2002 (15% vs 38% [P<.05]; 62% in both groups [P = .9], respectively). Similarly, oxaliplatin was used more frequently in younger patients in 2003 (22% vs 15%; P<.05), with a decrease in this difference noted by 2009 (64% vs 60%; P = .95). On multivariate analysis, older age (odds ratio, 0.65; P<.001) and a CCI >1 (odds ratio, 0.84; P<.001) were found to be associated with a lower likelihood of receiving combination chemotherapy.. In this commercially insured population, the percentage of older patients treated for mCRC was low, and the rate of chemotherapy adoption was found to lag behind that of younger patients. However, the percentage of older patients with comorbidities receiving therapy increased over time. Cancer 2016;122:3191-8. © 2016 American Cancer Society.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Comorbidity; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate; Young Adult

There is currently no standard treatment for metastatic urothelial cancer after failure of cisplatin-based therapy. The present retrospective study investigated the efficacy and safety of oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFOX) in locally advanced or metastatic urothelial cancer patients following cisplatin-based treatment. Thirty-three patients who had received one or two cisplatin-based regimens were treated with oxaliplatin (85 mg/m2) as a 2-h infusion on day 1, LV (200 mg/m2) as a 2-h infusion followed by bolus 5-FU (400 mg/m2) on day 1, or a 44-h continuous 5-FU (1,200 mg/m2) infusion. Patients were a mean of 67 years old with two involved organs. Metastases were mostly in the lung (43%), lymph nodes (51%) and liver (46%). Based on an intention-to-treat analysis, nine patients achieved a partial response, with an overall response rate of 27%. Eight (24%) patients had stable disease. Mean progression-free survival was 3 months and mean overall survival was 6.1 months. Toxicity was mild to moderate with grade 3 or 4 neutropenia, thrombocytopenia and neuropathy occurring in 5 (15%), 4 (12%) and 2 (6%) patients, respectively. This study demonstrated that oxaliplatin plus 5-FU/LV was a well-tolerated second-line regimen with moderate activity in patients pretreated with cisplatin-based therapeutics.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Retrospective Studies; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium

To identify suitable biomarkers of response to bevacizumab (BV) - it remains an open question. The measurement of serum vascular endothelial growth factor (VEGF) has been proposed as a predictive factor for this drug, even if literature data are contradictory.. We prospectively evaluated the role of BV, total and not BV-bound VEGF and angiopoietin-2 (Ang-2) serum levels as potential predictive factors of response for BV in combination with an oxaliplatin-based chemotherapy. BV, Ang-2, total and not BV-bound VEGF levels were measured at baseline, before 2(nd) and 5(th) cycle of oxaliplatin-based chemotherapy in 20 consecutive metastatic colorectal cancer patients.. Results were correlated to response to treatment. Variability in BV levels have been found, with decreased level in less responding patients. In particular, the concentration of BV increased of 3.96 ± 0.69 folds in serum of responsive patients after 3 more cycles of therapy compared to those with stable or progressive disease with a 0.72 ± 0.25 and 2.10 ± 0.13 fold increase, respectively. The determination of free and total VEGF demonstrated that the ratio between the two values, evaluated immediately before the 2(nd) and the 5(th) cycle of therapy, decreased from 26.65% ± 1.33% to 15.50% ± 3.47% in responsive patients and from 53.41% ± 4.75 to 34.95% ± 2.88% in those with stable disease. Conversely, in those with progression of disease, the ratio showed the opposite behavior coming up from 25.99% ± 5.23% to 51.71% ± 5.28%. The Ang-2 levels did not show any relationship.. Our data show that the ratio of not BV-bound VEGF to total VEGF serum and BV plasma concentrations for predicting the response to BV plus oxaliplatin-based chemotherapy could be a promising biomarker of response to BV.

Topics: Adult; Aged; Angiogenesis Inhibitors; Angiopoietin-2; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Vascular Endothelial Growth Factor A

Adding cetuximab to first-line FOLFIRI in the phase 3 CRYSTAL trial significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with KRAS wild-type (wt) or RAS wt metastatic colorectal cancer (mCRC). In this retrospective subgroup analysis of CRYSTAL, we investigated benefit of treatment in patients with KRAS wt or RAS wt tumors according to whether patients had liver-limited disease (LLD) or non-LLD, including assessing the role of cetuximab in downsizing metastases and conversion rates from initially unresectable to resectable disease.. PFS, OS, ORR, and R0 resection rates were analyzed according to treatment arm for the LLD and non-LLD subgroups.. Of the 367 patients with RAS wt tumors, 89 (24%) had LLD and 278 (76%) had non-LLD. Within the RAS wt LLD and non-LLD subpopulations, demographic and baseline characteristics were comparable between treatment arms. In patients with RAS wt LLD, adding cetuximab to FOLFIRI significantly improved PFS (hazard ratio [HR][95% CI] = 0.21[0.09-0.49]) and ORR (odds ratio [OR][95% CI] = 8.99[3.17-25.52]), and numerically improved OS (HR[95% CI] = 0.65[0.38-1.10]) and R0 resection rate (OR[95% CI] = 2.68[0.63-11.43]) relative to FOLFIRI alone. In patients with RAS wt non-LLD, adding cetuximab to FOLFIRI significantly improved PFS (HR[95% CI] = 0.65[0.46-0.93]), OS (HR[95% CI] = 0.71[0.54-0.93]), ORR (OR[95% CI] = 2.44[1.49-3.98]), and-numerically-R0 resection rate (OR[95% CI] = 5.94[0.79-44.88]). Similar results were obtained from the KRAS wt population.. Adding cetuximab to first-line FOLFIRI appears to improve clinical outcomes and R0 resection rates in KRAS wt and RAS wt mCRC patients with LLD as well as in those with non-LLD.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins p21(ras); Retrospective Studies

Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients.. With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival).. No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1).. Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; DNA Topoisomerases, Type I; Female; Fluorouracil; Genotype; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Response Evaluation Criteria in Solid Tumors; Survival Rate

Hypomethylation of Long Interspersed Nucleotide Element-1 (LINE-1) is associated with worse prognosis in colorectal cancer (CRC). However, little is known about the relevance of this marker for the prognosis and response to chemotherapy of metastatic and recurrent (advanced-stage) CRC. Our aim was therefore to investigate whether tumor LINE-1 hypomethylation correlates with patient survival and with response to 5-fluorouracil (5-FU)/ oxaliplatin (FOLFOX) chemotherapy in advanced-stage CRC.. The study included 40 CRC patients who developed metastasis or local recurrence after surgery and subsequently underwent FOLFOX therapy. Progression-free and overall survival were estimated using the Kaplan-Meier method. LINE-1 methylation levels in formalin-fixed and paraffin-embedded primary tumor tissues were measured by MethyLight assay and correlated with patient survival. In vitro analyses were also conducted with human colon cancer cell lines having different LINE-1 methylation levels to examine the effects of 5-FU and oxaliplatin on LINE-1 activity and DNA double-strand-breaks.. Patients with LINE-1 hypomethylation showed significantly worse progression-free (median: 6.6 vs 9.4 months; P = 0.02) and overall (median: 16.6 vs 23.2 months; P = 0.01) survival following chemotherapy compared to patients with high methylation. LINE-1 hypomethylation was an independent factor for poor prognosis (P = 0.018) and was associated with a trend for non-response to FOLFOX chemotherapy. In vitro analysis showed that oxaliplatin increased the LINE-1 score in LINE-1-expressing (hypomethylated) cancer cells, thereby enhancing and prolonging the effect of 5-FU against these cells. This finding supports the observed correlation between tumor LINE-1 methylation and response to chemotherapy in CRC patients.. Tumor LINE-1 hypomethylation is an independent marker of poor prognosis in advanced-stage CRC and may also predict non-response to combination FOLFOX chemotherapy. Prospective studies are needed to optimize the measurement of tumor LINE-1 methylation and to confirm its clinical impact, particularly as a predictive marker.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Caco-2 Cells; Cell Line, Tumor; Colorectal Neoplasms; DNA Methylation; Female; Fluorouracil; HCT116 Cells; Humans; Leucovorin; Long Interspersed Nucleotide Elements; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Prospective Studies; Survival Analysis; Treatment Outcome

Advanced gastric cancer patients with malignant ascites cannot tolerate S-1 plus cisplatin-containing therapy. The good toxicity profile of the FLTAX regimen(5-fluorouracil[5-FU]and Leucovorin[l-LV]combined with weekly paclitaxel) might make it a viable alternative treatment for these patients. We retrospectively evaluated the efficacy and safety of FLTAX in advanced gastric cancer patients.. Patients with advanced gastric cancer with malignant ascites were treated with 60mg/m2 paclitaxel, followed by 500 mg/m2 5-FU and 250 mg/m2 l-LV on days 1, 8, and 15. Treatment courses were repeated every 28 days. Patients were treated in our hospital from 2014 to 2016.. Three advanced gastric cancer patients with malignant ascites received the FLTAX regimen. The median age was 66 years(range 58-66). The median number of treatment courses was 2(range 1-20). The median progression-free survival and overall survival were 55(95%CI 24-.)and 272(95%CI 108-.)days, respectively. Observed Grade 3-4 adverse events were as follows: hyponatremia(1), anorexia(1), upper gastrointestinal hemorrhage(1), and thromboembolic event(1). No treatment-related death occurred.. FLTAX demonstrated an acceptable toxicity profile, and may be a good option for gastric cancer patients with malignant ascites.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Ascites; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Paclitaxel; Retrospective Studies; Stomach Neoplasms

Primary adenocarcinoma of the bladder is a very rare disease that is difficult to treat. In this paper, we report the second case in the literature with primary mucinous adenocarcinoma of the bladder which showed complete response to FOLFOX4 (fluorouracil, leucovorin, oxaliplatin) chemotherapy regimen.. A 41-year-old man was admitted to our hospital with a diagnosis of primary adenocarcinoma of the bladder. Due to the similarity in histology with colon carcinoma, a FOLFOX4 regimen was started. Complete response was achieved at the end of this treatment. Today the patient is free of local or systemic disease.. FOLFOX4 regimen may be a treatment option for primary adenocarcinoma of the bladder.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Immunohistochemistry; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Radiography, Thoracic; Tomography, X-Ray Computed; Treatment Outcome; Urinary Bladder Neoplasms

Nutrition and immunity significantly affect the progression of cancer in cancer patients. Therefore, the evaluation of the nutritional and immune status would be useful as a prognostic factor and to determine the optimal treatment strategy for patients with unresectable metastatic colorectal cancer who are receiving chemotherapy. The aim of this retrospective study was to evaluate the prognostic significance of the nutritional and immune status in patients with unresectable metastatic colorectal cancer treated with chemotherapy.. We retrospectively reviewed 80 patients with colorectal cancer. A total of 22 patients had metachronous unresectable cancer, and 58 patients had synchronous unresectable cancer. All patients underwent combination chemotherapy with oxaliplatin or irinotecan plus 5-fluorouracil/leucovorin as first-line chemotherapy. We then examined the correlations between the Onodera's prognostic nutritional index (OPNI) and the patients' clinicopathological features. The OPNI was calculated as follows: 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm(3)). According to the receiver operating characteristic (ROC) curve analysis, the cutoff value for OPNI was 44.5.. Patients with a pretreatment OPNI of ≧44.5 demonstrated a longer OS than those with a pretreatment OPNI of <44.5. Moreover, we categorized these patients into four groups according to the combination of the pre- and post-treatment OPNI. The patients in the group with both OPNIs ≥44.5 exhibited a better prognosis compared to the other group (p = 0.001).. The OPNI is considered to be a useful marker for predicting the long-term outcome in patients who receive chemotherapy for unresectable metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Nutrition Assessment; Nutritional Status; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate

The optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and bolus fluorouracil plus leucovorin]).. Tumor measurements and progression-free survival (PFS) data were obtained for 1,471 patients; 1,002 had consistently measured tumors and were resampled (5,000 replicates) to simulate two-arm, randomized phase II trials with α = 0.10 (one sided) and 20 to 80 patients per arm. End points included log ratio of tumor size at 6, 12, and 18 weeks relative to baseline; time to tumor growth (TTG), estimated using a nonlinear mixed-effects model; and PFS. Arms were compared using rank sum tests for log ratio and TTG and a log-rank test for PFS.. For FOLFOX versus IFL, TTG and PFS had similar power, with both exceeding the power of log ratio at 18 weeks; for FOLFOX versus IROX, TTG and log ratio at 18 weeks had similar power, with both exceeding the power of PFS. The best end points exhibited > 80% power with 60 to 80 patients per arm.. TTG is a powerful end point for randomized phase II trials of cytotoxic therapies in metastatic colorectal cancer; it was either comparable or superior to PFS and log ratio at 18 weeks. Additional studies will be needed to clarify the potential of TTG as a phase II end point.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease Progression; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Treatment Outcome; Tumor Burden

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disseminated Intravascular Coagulation; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy.. Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon.. Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX.. After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoradiotherapy; Disease-Free Survival; Female; Fluorouracil; Humans; Imaging, Three-Dimensional; Irinotecan; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Retrospective Studies; Spiral Cone-Beam Computed Tomography; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoplasm Metastasis; Organoplatinum Compounds

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Neoplasm Metastasis; Randomized Controlled Trials as Topic

The addition of bevacizumab to fluorouracil-based chemotherapy is a standard of care for previously untreated metastatic colorectal cancer. Continuation of bevacizumab beyond progression is an accepted standard of care based on a 1.4-month increase in median overall survival observed in a randomized trial. No United States-based cost-effectiveness modeling analyses are currently available addressing the use of bevacizumab in metastatic colorectal cancer. Our objective was to determine the cost effectiveness of bevacizumab in the first-line setting and when continued beyond progression from the perspective of US payers.. We developed two Markov models to compare the cost and effectiveness of fluorouracil, leucovorin, and oxaliplatin with or without bevacizumab in the first-line treatment and subsequent fluorouracil, leucovorin, and irinotecan with or without bevacizumab in the second-line treatment of metastatic colorectal cancer. Model robustness was addressed by univariable and probabilistic sensitivity analyses. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs).. Using bevacizumab in first-line therapy provided an additional 0.10 QALYs (0.14 life-years) at a cost of $59,361. The incremental cost-effectiveness ratio was $571,240 per QALY. Continuing bevacizumab beyond progression provided an additional 0.11 QALYs (0.16 life-years) at a cost of $39,209. The incremental cost-effectiveness ratio was $364,083 per QALY. In univariable sensitivity analyses, the variables with the greatest influence on the incremental cost-effectiveness ratio were bevacizumab cost, overall survival, and utility.. Bevacizumab provides minimal incremental benefit at high incremental cost per QALY in both the first- and second-line settings of metastatic colorectal cancer treatment.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Cost-Benefit Analysis; Fluorouracil; Humans; Leucovorin; Markov Chains; Neoplasm Metastasis; Organoplatinum Compounds; Outcome Assessment, Health Care; Oxaliplatin; Quality-Adjusted Life Years; Survival Analysis; United States

We present the case of a 43-year-old-man with wild-type KRAS and BRAF colorectal adenocarcinoma that was metastatic to the liver and lung. The patient initially received neoadjuvant chemotherapy with FOLFOX and bevacizumab, followed by surgical resection of the primary tumor and hepatic metastases. His disease recurred shortly after surgery and he was treated with FOLFIRI plus the anti-EGFR antibody cetuximab. After this regimen failed to arrest his disease progression, treatment with FOLFIRI in combination with another anti-EGFR antibody, panitumumab was started. While on this therapy, the patient's lung nodules remained largely stable but metastatic lesions within the liver continued to progress. Our case highlights the differences between panitumumab and cetuximab, and contemplates the possible explanations for this patient's apparently heterogeneous disease progression within the liver despite stabilization of multiple pulmonary nodules.

Topics: Adenocarcinoma; Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Panitumumab

To compare the costs of first-line treatment with panitumumab + FOLFOX in comparison to cetuximab + FOLFIRI among patients with wild-type (WT) RAS metastatic colorectal cancer (mCRC) in the US.. A cost-minimization model was developed assuming similar treatment efficacy between both regimens. The model estimated the costs associated with drug acquisition, treatment administration frequency (every 2 weeks for panitumumab, weekly for cetuximab), and incidence of infusion reactions. Average anti-EGFR doses were calculated from the ASPECCT clinical trial, and average doses of chemotherapy regimens were based on product labels. Using the medical component of the consumer price index, adverse event costs were inflated to 2014 US dollars, and all other costs were reported in 2014 US dollars. The time horizon for the model was based on average first-line progression-free survival of a WT RAS patient, estimated from parametric survival analyses of PRIME clinical trial data.. Relative to cetuximab + FOLFIRI in the first-line treatment of WT RAS mCRC, the cost-minimization model demonstrated lower projected drug acquisition, administration, and adverse event costs for patients who received panitumumab + FOLFOX. The overall cost per patient for first-line treatment was $179,219 for panitumumab + FOLFOX vs $202,344 for cetuximab + FOLFIRI, resulting in a per-patient saving of $23,125 (11.4%) in favor of panitumumab + FOLFOX.. From a value perspective, the cost-minimization model supports panitumumab + FOLFOX instead of cetuximab + FOLFIRI as the preferred first-line treatment of WT RAS mCRC patients requiring systemic therapy.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Costs and Cost Analysis; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Models, Econometric; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; ras Proteins

Combination chemotherapy of 5 fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin, mainly FOLFOX regimens, has shown considerable antitumor activity and a tolerable toxicity profile in gastric cancer. The goal of this study was to retrospectively compare the efficacy and toxicity of modified FOLFOX-6 (mFOLFOX6) regimen in advanced gastric cancer (AGC) patients with good and poor performance status (PS).. AGC patients receiving the mFOLFOX6 regimen including oxaliplatin 85 mg/m2, bolus of 5-FU 400 mg/m2 and LV 400 mg/m2 on the first day, followed by 2400mg/m2 of 5- FU as a continious infusion over 46 hour for first-line treatment were eligible for the study.. A total 58 patients with a median age of 59.5 (32-81) were included. The median follow up of the study was 9.2 months. Thirty patients (51.7%) with an ECOG PS 0-1 were assigned to the good PS arm, while 28 patients (48.3%) with ECOG PS 2 were in the poor PS arm. Overall response rates were 36.6 and 28.8%, respectively (p=0.91). Median PFS was 6.7 and 6.3 months in good PS and poor PS arms (p=0.50) and median OS was 9.6 and 10.4 months (p=0.55). As compared with good PS arm, poor PS arm was associated with more grade 3-4 neutropenia and anemia. Dose reduction and dose delays were also significantly higher.. In this study, mFOLFOX6 was similarly effective in both arms. Although hematologic toxicity was significantly higher in patients with poor PS, it remained manageable. Our results suggest that this regimen may be an effective treatment option for AGC patients with poor PS.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Stomach Neoplasms; Survival Rate

Bevacizumab is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer (mCRC). Although chemotherapy plus bevacizumab has led to improve outcomes for mCRC patients and is a common choice for first-line treatment of mCRC, previous research has established no prominent biomarker that can help to select patients who may benefit from bevacizumab in order to improve cost-effectiveness and therapeutic outcomes. The aim of this study was to compare pre- and post-therapeutic VEGF immunohistochemical (IHC) expression in mCRC patients treated with FOLFIRI plus bevacizumab to identify its potential role as a predictive biomarker.. A total of 57 mCRC patients who underwent FOLFIRI combined with bevacizumab chemotherapy as a first-line neoadjuvant regimen were enrolled and clinical outcome data analyzed.. Low post-therapeutic VEGF expression (P < 0.001) and decreased peri-therapeutic VEGF expression (P < 0.001) were significantly predictive factors of responders. Furthermore, the 6-month progression-free survival (PFS) rate in mCRC patients with decreased peri-therapeutic VEGF expression was significantly better than the rate for those patients with no peri-therapeutic VEGF expression alterations (P = 0.033).. Decreased peri-therapeutic VEGF expression in mCRC patients could probably be used to predict responsiveness to bevacizumab and subsequent PFS in clinical practice.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Down-Regulation; Female; Fluorouracil; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Predictive Value of Tests; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A

To retrospectively compare the efficacy of two irinotecan-based chemotherapy regimens combined with bevacizumab in first-line therapy of metastatic colorectal cancer (mCRC).. The data of 558 patients with mCRC treated with first-line bevacizumab plus irinotecan-containing regimen were obtained from the national CORECT registry that collects data of all patients with mCRC treated with targeted-agents. The treatment outcomes of patients treated with bevacizumab plus irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) were compared to patients treated with bevacizumab plus irinotecan and capecitabine (XELIRI).. Among 4,312 patients with CRC treated with bevacizumab, only 13% (558) received irinotecan-based chemotherapy. No significant differences were observed in terms of progression-free survival and overall survival between FOLFIRI and XELIRI groups. Moreover, the toxicity of both regimens was also comparable.. This retrospective analysis confirms the comparable activity of FOLFIRI and XELIRI regimens when combined with bevacizumab.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Czech Republic; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Treatment Outcome

Aflibercept increased overall survival with acceptable tolerability in metastatic colorectal cancer (mCRC) when it was used in combination with FOLFIRI after progression on a first-line oxaliplatin regimen (VELOUR study). The safety profile of aflibercept in day-to-day clinical practice was assessed.. A named patient program provided early access to aflibercept to mCRC patients in Spain before its commercialization. Patients received aflibercept 4 mg/kg intravenous + FOLFIRI every 2 weeks as second-line treatment. A descriptive safety analysis was conducted.. Data from 89 mCRC patients were analyzed (male: 61.8%; median age: 62 years [interquartile range: 55, 67]; Eastern Cooperative Oncology Group 0 - 1: 95.5%). Fifty four (60.7%) patients presented ≥ 2 metastasis [liver (83.1%), lung (44.9%) or lymph nodes (33.7%)]. Most patients had previously received bevacizumab (60.7%) or anti-EGFR (19.1%) therapy. Patients received a median of 6.0 (interquartile range: 4, 13) cycles of FOLFIRI + aflibercept. Most grade ≥ 3 adverse events (AEs) were reported during the initial cycles of treatment. AEs possibly related to treatment occurred in 39 (43.8%) patients. Common grade ≥ 3 treatment-related AEs were neutropenia (7.9%), diarrhea (4.5%) and hypertension (3.4%).. In clinical practice, aflibercept + FOLFIRI is well tolerated, with a manageable toxicity profile. The safety results confirm the findings from the confirmatory VELOUR trial.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Spain

In patients with metastatic colon cancer, response to first line chemotherapy is a strong predictor of overall survival (OS). Currently, oncologists lack diagnostic tests to determine which chemotherapy regimen offers the greatest chance for response in an individual patient. Here we present the results of gene expression analysis for two genes, ERCC1 and TS, measured with the commercially available ResponseDX: Colon assay (Response Genetics, Los Angeles, CA) in 41 patients with de novo metastatic colon cancer diagnosed between July 2008 and August 2013 at the University of California, San Diego. In addition ERCC1 and TS expression levels as determined by RNAseq and survival data for patients in TCGA were downloaded from the TCGA data portal. We found that patients with low expression of ERCC1 (n = 33) had significantly longer median OS (36.0 vs. 10.1 mo, HR 0.29, 95% CI .095 to .84, log-rank p = 9.0x10-6) and median time to treatment to failure (TTF) following first line chemotherapy (14.1 vs. 2.4 mo, HR 0.17, 95% CI 0.048 to 0.58, log-rank p = 5.3x10-4) relative to those with high expression (n = 4). After accounting for the covariates age, sex, tumor grade and ECOG performance status in a Cox proportional hazard model the association of low ERCC1 with longer OS (HR 0.18, 95% CI 0.14 to 0.26, p = 0.0448) and TTF (HR 0.16, 95% CI 0.14 to 0.21, p = 0.0053) remained significant. Patients with low TS expression (n = 29) had significantly longer median OS (36.0 vs. 14.8 mo, HR 0.25, 95% CI 0.074 to 0.82, log-rank p = 0.022) relative to those with high expression (n = 12). The combined low expression of ERCC1/TS was predictive of response in patients treated with FOLFOX (40% vs. 91%, RR 2.3, Fisher's exact test p = 0.03, n = 27), but not with FOLFIRI (71% vs. 71%, RR 1.0, Fisher's exact test p = 1, n = 14). Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Analysis; Thymidylate Synthase

To observe the clinical efficacy of cetuximab plus chemotherapy in the treatment of metastatic colorectal carcinoma.. Clinicopathological data of 128 patients with metastatic colorectal cancer admitted in the Department of Oncology, Chinese PLA General Hospital from 2008 to June 2012 were analyzed retrospectively. Among them, 91 patients received cetuximab as the first-line therapy and 37 in the second-line or more-line therapy. The chemotherapy regimens included oxaliplatin-based therapy (FOLFOX/XELOX), irinotecan-based therapy (FOLFIRI/XELIRI) and fluorouracil-based therapy (Xeloda). The efficacy was evaluated according to RECIST 1.0 criteria. The remission rate, control rate and time to disease progression were compared among patients receiving cetuximab combined with different chemotherapy regimens in different periods.. The disease control rate of cetuximab applied in the first-line treatment was higher than that of the second-line or more-line [85.9% (61/71) vs. 59.3% (16/27), P=0.004]. The disease control rate of the group treated with cetuximab plus oxaliplatin-based chemotherapy was much higher compared to the other two groups [91.1% (41/45) vs. 68.1% (32/47), 4/6, P=0.021]. But there were no significant differences among three regimens in the terms of overall response rate (all P>0.05). The median time to progression of groups with cetuximab plus irinotecan, oxaliplatin or capecitabine was 7.8 months, 8.5 months and 5.2 months respectively. The median time to progression of cetuximab combined with chemotherapy in the first-line treatment and the second-line or more-line was 8.2 and 7.7 months respectively. However, the differences were not statistically significant (P>0.05).. Cetuximab in combination with oxaliplatin-based chemotherapy is recommended as the first-line application in the treatment of metastatic colorectal carcinoma patients, because it is helpful to improve the rate of disease control.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Cetuximab; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Retrospective Studies; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Costs; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Ramucirumab; Randomized Controlled Trials as Topic; United States

To compare efficacy and toxicity of bolus application of chemotherapy protocol, oxaliplatin, fluorouracil (bolus), leucovorin (folfox) between two groups of patients in the therapy of metastatic colorectal carcinoma (mCRC).. A total of 63 patients were treated for mCRC in the period January 2009 - January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients) and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 - January 2006 (second group, 33 patients). The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D), 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS), progression free survival, hematological and non-hematological toxicity .. Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time.. Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies; Treatment Outcome

Pharmacoeconomic assessments are a part of the decision process not only during reimbursement setting, but in clinical practice as well. The presented cost-effectiveness analysis assesses panitumumab+mFOLFOX6 vs. bevacizumab+mFOLFOX6 in 1st line treatment of patients with wildtype RAS metastatic colorectal cancer (mCRC) in the Czech environment.. The adaptation of a Markov model considers the healthcare perspective; clinical data (efficacy, healthcare utilization and adverse events) are derived from a head-to-head comparison (PEAK study). Health states included in the model: progression free on treatment, progression (with/ without active treatment), resection of metastases, disease-free after successful resection and death. Actual reimbursement levels were used to estimate costs, published literature to estimate duration of 2nd line treatment. The analysis assumes a lifetime horizon; uncertainty was limited by performing one-way and probabilistic sensitivity analyses. Analysis outcomes are life-years gained (LYG) and quality-adjusted life-years (QALYs).. Panitumumab+mFOLFOX6 is more effective and more costly in 1st line patients with wildtype RAS mCRC. Incremental costs per QALY are 837,270 CZK, per LYG 615,022 CZK; however, below the willingness-to-pay threshold applied in the Czech Republic.. Panitumumab+mFOLFOX6 is cost-effective in 1st line treatment of patients with wildtype RAS mCRC compared to bevacizumab+mFOLFOX6 in the Czech setting.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Cost-Benefit Analysis; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Quality-Adjusted Life Years

To assess the feasibility and effectiveness of quantitative intravoxel incoherent motion (IVIM) of Diffusion-weighted imaging (DWI) in the assessment of liver metastases treated with targeted chemotherapy agents.. 12 patients with unresectable liver metastases from colorectal cancer were enrolled and received neoadjuvant FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab therapy. DWI was performed for 36 metastases at baseline and after 14 days from starting the treatment. In addition to the basic IVIM metrics, the product between pseudo-diffusivity and perfusion fraction was considered as a descriptor roughly analogous to the flow. Median diffusion parameters of Region of Interest (ROI) were used as representative values for each lesion. Normalized parameters in comparison with the median value of spleen were also collected. The percentual change of the diffusion parameters was calculated. The response to chemotherapy was evaluated according the Response Evaluation Criteria in Solid Tumors (RECIST) as calculated on whole-body CT scan obtained three months after treatment. Mann Whitney test and Receiver operating characteristic (ROC) analysis were performed.. 24 lesions were categorized as responding and 12 as not responding. There was no statistically significant difference among absolute and normalized diffusion parameters between the pretreatment and the post-treatment findings. Instead, the perfusion fraction (fp) values showed a statistical difference between responder and non-responder lesions: sensitivity and specificity of fp variation was 62% and 93%, respectively.. IVIM parameters represent a valuable tool in the evaluation of the anti-angiogenic therapy in patients with liver metastases from colorectal cancer. A percentage change of fp represents the most effective DWI marker in the assessment of tumor response.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Diffusion Magnetic Resonance Imaging; Early Detection of Cancer; Female; Fluorouracil; Humans; Image Processing, Computer-Assisted; Leucovorin; Liver Neoplasms; Male; Middle Aged; Motion; Neoplasm Metastasis; Perfusion; ROC Curve; Spleen; Tomography, X-Ray Computed; Whole Body Imaging

We investigate whether three common polymorphisms in ERCC1 and ERCC2 are predictor factors for the chemotherapy response, as well as the clinic outcome of patients with gastric cancer. Between May 2011 and May 2013, 263 patients with gastric cancer who were newly diagnosed by histopathology were enrolled in our study. Genotyping of the ERCC1 rs11615 and rs3212986, and ERCC2 rs1799793 polymorphisms were conducted by the polymerase chain reaction-restriction fragment length polymorphism assay. Patients carrying the TT genotype and TT+CT genotype of ERCC1 rs11615 were associated with poorer response to chemotherapy and shorter survival times when compared with the CC genotype. In conclusion, our results suggested that the ERCC1 rs11615 polymorphism in the DNA repair pathways can be used as predictive factors to the clinical outcome of patients with gastric cancer.

Topics: Aged; Alleles; Antineoplastic Combined Chemotherapy Protocols; DNA Repair; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Genetic Variation; Genotype; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Prognosis; Proportional Hazards Models; Stomach Neoplasms; Treatment Outcome; Xeroderma Pigmentosum Group D Protein

Docetaxel-cisplatin-5-FU chemotherapy is superior to 5-FU-cisplatin in terms of response rate and survival in advanced gastric cancer (AGC), but is more toxic. Oxaliplatin is better tolerated than cisplatin, which it can effectively replace in this setting. We hypothesize that incorporating docetaxel into a simplified FOLFOX regimen should be a tolerable and effective option in first-line treatment of AGC.. Data were collected at six French centers from patients with metastatic or local AGC who received docetaxel, fluorouracil, leucovorin, or oxaliplatin (TEF) as first-line treatment. TEF was administered as follows: docetaxel (50 mg/m(2)), oxaliplatin (85 mg/m(2)), and leucovorin (40 mg/m(2)) on day 1, and 5-FU continuous infusion for 48 h (2400 mg/m(2)) every 2 weeks.. Forty-one patients were enrolled. Performance status was grade 0 and 1 in respectively 27 and 58 % of patients; 17 patients had adenocarcinoma of the gastroesophageal junction; 37 patients had metastatic disease, 22 had a poorly differentiated or diffuse type. Objective response rate was 66 %, with a complete response in two patients (5 %). Median progression-free survival and overall survival were respectively 6.3 and 12.1 months. Tolerability was acceptable with no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (30 %) and neuropathy (12.5 %). Curative intent surgery after response to TEF was performed in seven patients (17 %).. TEF is an effective first-line treatment with an acceptable toxicity profile for patients with AGC. It may allow curative resection in initially unresectable patients. TEF should now be evaluated in prospective randomized trials.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Esophagogastric Junction; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Stomach Neoplasms; Survival Rate; Taxoids

Past reports have suggested that the addition of bevacizumab (BV) to oxaliplatin combined with 5-fluorouracil (5-FU) and folinic acid (leucovorin) (FOLFOX4) provides a limited survival benefit in metastatic colorectal cancer (mCRC). Our study aimed to evaluate the survival benefits of a FOLFOX4 + BV regimen.. Patients with mCRC who started treatment between April 2005 and July 2008 were evaluated in this retrospective cohort study. Patients received FOLFOX4, or FOLFOX4 + BV after the approval of BV in 2007. The two cohorts treated before and after BV approval were compared. Primary end-points were progression-free survival (PFS), overall survival (OS) and response rate (RR).. A total of 213 patients received either FOLFOX4 (n = 128) or FOLFOX4 + BV (n = 85). For FOLFOX4 and FOLFOX4 + BV respectively, median PFS was 9.9 and 17.0 months (HR, 0.58; 95% CI, 0.42-0.82; P = 0.002), median OS was 20.5 and 38.8 months (HR, 0.49; 95% CI, 0.34-0.71; P < 0.001), respectively. Patients who received 5-fluorouracil plus leucovorin (FL) as maintenance therapy during oxaliplatin suspension in both FOLFOX4 (n = 6) and FOLFOX4 + BV (n = 46) groups showed a trend to improved median PFS and median OS.. The additive effect and potential survival benefits of adding BV to the FOLFOX4 regimen in first-line treatment of mCRC were demonstrated. Maintenance FL during suspension of oxaliplatin appeared to be an important factor in better survival.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Electronic Health Records; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Proportional Hazards Models; Retrospective Studies; Treatment Outcome; Young Adult

Either oxaliplatin- or irinotecan-containing regimen could receive a good effectiveness in patients with metastatic colorectal cancer as the first-line chemotherapy, but not all patients would benefit from the treatment they have received. This study was to investigate the role of single nucleotide polymorphisms (SNPs) of methylenetetrahydrofolate reductase (MTHFR) and ATP-binding cassette sub-family G member 2 (ABCG2) in selecting the most appropriate treatment for individual patients. Ninety-two metastatic colorectal cancer patients treated with first-line 5-fluoropyrimidine (5-FU), leucovorin, and oxaliplatin (FOLFOX), capecitabine, and oxaliplatin (XELOX) and sixty-two patients receiving 5-FU, leucovorin, and irinotecan (FOLFIRI) were reviewed. The SNPs of MTHFR and ABCG2 were detected using gene sequencing method after DNA PCR amplification, which was extracted from peripheral blood karyocytes. Clinical characteristics and gene polymorphisms were evaluated in univariate and multivariate analysis as predictive factors for response rate (RR) and progression-free survival (PFS). In patients bearing 2-4 genotypes of MTHFR 677C/C, MTHFR 1298 A/C or C/C, ABCG2 34G/G, and ABCG2 421C/A or A/A, those who received oxaliplatin-based chemotherapy achieved a higher RR (41.7 vs. 18.8 %, P = 0.027) and longer median PFS (mPFS) than irinotecan-based therapy [8.9 vs. 7.1 m, FOLFIRI: hazard ratio (HR) = 1.722, 95 % confidence interval (CI) 1.026-2.892, P = 0.040, compared with FOLFOX/XELOX]; on the contrary, patients carrying 0 or 1 above genotype exhibited better outcomes after receiving FOLFIRI chemotherapy (mPFS: 9.3 vs. 6.4 m, FOLFIRI: HR = 0.422, 95 % CI 0.205-0.870, P = 0.019, compared with FOLFOX/XELOX). Combination of SNPs with MTHFR and ABCG2 may play a role in helping clinicians to select first-line chemotherapy for patients with metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Genotype; Humans; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Neoplasm Proteins; Organoplatinum Compounds; Oxaloacetates; Pharmacogenetics; Polymorphism, Single Nucleotide; Recurrence; Retrospective Studies

The treatment of metastatic colon cancer (mCC) utilizes either combination therapies or sequential monotherapy followed by combination therapy in subsequent lines of treatment. Patients often receive therapy consisting of oxaliplatin with intravenous 5-fluoruacil (5-FU) (FOLFOX) or oral capecitabine (CAPOX). A retrospective analysis was performed comparing median dose intensity (MDI), overall survival (OS), progression-free survival (PFS), and toxicity profiles of these two regimens in mCC.. One hundred twenty-two mCC patients (pts) received either FOLFOX6 (n = 46) or CAPOX (n = 76). Age, gender, and Eastern Cooperative Oncology Group (ECOG) performance status at diagnosis were balanced between groups. MDI was compared by calculating a percent of target dose achieved in the average cycle for each patient and taking the median of this value.. Oxaliplatin MDI trended towards being lower in those treated with CAPOX compared to FOLFOX (87.5 vs 93 %, p = 0.0874), and capecitabine (CA) MDI was significantly lower than 5-FU (82.0 vs 100 %, p < 0.0001). There was a trend to more dose-limiting toxicities (DLTs) in pts treated with CAPOX (68.42 vs 54.35 %, p = 0.1268), and grade ≥ 2 toxicities were more frequent in CAPOX-treated pts (38.16 vs 15.22 % of patients, p = 0.0079). Survival analysis demonstrated trends towards improved median OS (9.86 vs 7.46 months, p = 0.1183) and median PFS (4.34 vs 3.33 months, p = 0.1674) with CAPOX. In multivariate analysis, CAPOX was associated with improved OS (p = 0.0156, hazard ratio (HR) 0.559) and disease-free survival (DFS) (p = 0.0094, HR 0.549).. Patients treated with CAPOX received lower doses of oxaliplatin and fluoropyrimidine compared to FOLFOX and had toxicities of higher grade but did not have worsened clinical outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Dose-Response Relationship, Drug; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate

To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).. A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.. For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.. This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Gene Frequency; Genetic Variation; Genotype; HLA Antigens; HLA-B Antigens; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Prognosis; Receptors, KIR; Receptors, KIR3DL1; Treatment Outcome

The robustness of the circadian timing system (CTS) was correlated to quality of life and predicted for improved survival in cancer patients. However, chemotherapy disrupted the CTS according to dose and circadian timing in mice. A continuous and repeated measures longitudinal design was implemented here to characterize CTS dynamics in patients receiving a fixed circadian-based chemotherapy protocol. The rest-activity rhythm of 49 patients with advanced cancer was monitored using a wrist actigraph for 13 days split into four consecutive spans of 3-4 days each, i.e., before, during, right after and late after a fixed chronotherapy course. The relative amount of activity in bed vs. out of bed (I

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Circadian Rhythm; Fatigue; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Monitoring, Physiologic; Motor Activity; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Rest; Weight Loss

Typically, bevacizumab is initially infused for 90 min, then for 60 min, and subsequently for 30 min. The objective of the present study was to evaluate the safety profile of a short infusion of bevacizumab in Japanese colorectal cancer patients.. The records of 58 patients who received bevacizumab (5 mg/kg) from June 2010 to September 2010 were reviewed. Bevacizumab was administered for 30 min at the first time. If patients had no infusion reaction, the infusion time was shortened to 10 min.. None of the 58 patients who received bevacizumab experienced an infusion reaction (95% confidence interval 0-6.2). The only serious adverse event related to bevacizumab infusion was grade 3 proteinuria in 2 patients.. Short infusion of bevacizumab for 30 min the first time and 10 min is safe and feasible.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies

Both 5-FU and oxaliplatin have been used as single agents in patients with colorectal cancer and severe liver dysfunction, but the combination of these drugs has not yet been investigated. A 67-year-old man diagnosed with colorectal cancer in 2008 presented in April 2011 to Appalachian Regional Healthcare Cancer Center with obstructive jaundice and weight loss. Imaging studies were compatible with a liver mass and dilatation of the intrahepatic bile ducts. A liver biopsy confirmed metastatic colorectal cancer. Because his total bilirubin level was 23.1 mg/dL, a percutaneous catheter was placed in May 2011. His total bilirubin level decreased to 5.9 mg/dL, but then increased to 9.4 mg/dL in June 2011. He was started on a FOLFOX regimen, with a 50% dose reduction of 5-FU bolus (200 mg/m(2)) and continuous infusion (1200 mg/m(2)) over 46 hours, and a 15% dose reduction of oxaliplatin (75 mg/m(2)) every 2 weeks. He tolerated this regimen very well, with normalization of his bilirubin level, a significant decrease in his tumor markers, and a partial response seen on PET/CT scan. His only significant toxicity was a grade 2 stomatitis. He received 21 cycles of FOLFOX, and was later switched to cetuximab treatment after disease progression. These findings suggest that FOLFOX might be effective in metastatic colon cancer with severe liver dysfunction, with minimal toxicity, and deserves further investigation.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bilirubin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Function Tests; Liver Neoplasms; Magnetic Resonance Imaging; Male; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

Endothelin-1 (ET-1) and asymmetric dimethylarginine (ADMA) play a major role in tumor growth and metastasis. Our aim was to determine whether there is any association between these endothelial parameters and tumor markers with the clinical outcome of bevacizumab-treated metastatic colorectal cancer (mCRC) patients in terms of response and survival. Pretreatment serum levels of ET-1, ADMA, carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 were measured in 36 chemotherapy-naive mCRC patients treated with first-line bevacizumab-based therapy. Additionally, after first cycle of treatment, serum levels of these parameters were reanalyzed. Lower baseline serum ET-1 and ADMA levels were observed in patients responding to bevacizumab-based treatment (respectively, p = 0.037, p = 0.034). Median progression-free survival (PFS) (11 vs. 6 months, p = 0.012) and overall survival (OS) (28 vs 9 months; p = 0.007) were significantly shorter in patients with high pretreatment ET-1 levels. There was a significant decrease in ET-1 and CEA levels after first treatment (p = 0.020, p = 0.012), while ADMA and CA 19-9 levels were not significantly changed. Patients with decreased posttreatment ET-1 levels were shown to have inferior PFS (6 vs 11 months, p = 0.022), but no statistically significant difference was shown with respect to OS (p = 0.141). The effect of bevacizumab on endothelin axis including the biologic basis of decreasing ET-1 levels due to bevacizumab treatment and its association with inferior outcome has to be clarified in prospective trials.

Topics: Adenocarcinoma; Adult; Aged; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; CA-19-9 Antigen; Camptothecin; Capecitabine; Carcinoembryonic Antigen; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaloacetates; Prospective Studies; Treatment Outcome

Pancreatic adenocarcinoma is the 10th most common malignancy in the United States but is responsible for the 4th most cancer related deaths. This disease can only be potentially cured through early discovery and complete surgical resection. Unfortunately, nearly half of patients have metastatic spread at presentation. Combination chemotherapy with FOLFIRINOX or gemcitabine with nab-paclitaxel can prolong survival in selected patients, but at the cost of significant toxicity. In the 2014 ASCO Gastrointestinal Cancers Symposium, several studies were presented that focus on the management of metastatic pancreatic cancer. A phase II trial by Le et al. (Abstract #177) found that the addition of CRS-207, a strain of Listeria modified to stimulate an anti-tumor immune response, improves survival in patients being treated with GVAX. Goldstein et al. (Abstract #178) presented a post-hoc survival analysis for the phase III MPACT trial that shows the addition of nab-paclitaxel to gemcitabine produces a persistent survival benefit. Ramanathan et al. (Abstract #224) demonstrated that, with appropriate dose adjustments and delays, induction nab-paclitaxel and gemcitabine followed by mFOLFIRINOX consolidation is a feasible treatment option for metastatic pancreatic cancer. Despite these advances, it is imperative that we continue to work towards developing additional treatment options that are better tolerated and further prolong survival for these patients. This highlight article focuses on the first-line therapy of metastatic pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Drug Therapy; Drug Therapy, Combination; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Treatment Outcome

The aim of this study was to compare the outcomes in colorectal cancer (CRC) patients with synchronous unresectable metastases who received either primary tumor resection (PTR) or chemotherapy as the first treatment and to investigate the clinical course of asymptomatic patients who received chemotherapy as the first treatment.. We retrospectively analyzed 324 CRC patients with synchronous unresectable metastases. Overall survival (OS) was analyzed for the two groups (upfront PTR group [n = 72] vs. upfront chemotherapy group [n = 252]). Surgical morbidity and mortality were recorded. In the asymptomatic patients who received upfront chemotherapy, the incidences of primary tumor-related complications were analyzed.. In patients who underwent PTR as the first treatment, the median OS period was superior to those who received upfront chemotherapy (17.2 vs. 13.6 months, P = 0.002). In the PTR group, surgical morbidity and mortality were 11.6% and 1.9%, respectively. Of the 252 asymptomatic patients, the incidence of primary tumor-related complications was 35%. Emergent surgery was ultimately done in 14% of the 252 patients.. CRC patients with synchronous unresectable metastases who underwent PTR followed by chemotherapy had significantly longer survival times compared to patients who received chemotherapy as the first treatment.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asymptomatic Diseases; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaloacetates; Palliative Care; Rectum; Retrospective Studies; Survival Rate; Treatment Outcome

Information on prognostic factors for metastatic colorectal cancer is an important basis for planning the treatment and predicting the outcomes of the patients; however, it has not been well established. The aim of this study was to identify factors that predict results of chemotherapy and to establish a plan for treatment of patients whose tumors are inoperable due to metastatic colorectal cancer.. We conducted a retrospective review of records from 75 patients treated for colorectal cancer in Kosin University Gospel Hospital, from October 2004 to September 2008. Patients with inoperable tumors due to metastasis at the time of diagnosis who were treated with oxaliplatin or irinotecan as the first-line treatment were included in this study. We investigated the factors that might have an effect on overall survival.. A total of 75 patients were included in this study. Results of univariate analysis showed that hemoglobin (Hb) ≥10 g/dL at the time of diagnosis, no increase in CEA on the follow-up examination after chemotherapy, chemotherapy plus surgery, and better response to chemotherapy were significant prognostic factors. Results of multivariate analysis showed that Hb ≥10 g/dL at the time of diagnosis (p<0.001), surgery after chemotherapy (p=0.001), and better response to chemotherapy (p=0.014) were significant prognostic factors.. In this study, Hb ≥10 g/dL at the time of diagnosis, surgery after chemotherapy, and better response to chemotherapy were significant prognostic factors for metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Hemoglobins; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Odds Ratio; Organoplatinum Compounds; Prognosis; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Renal Dialysis

We report a rare case of a 67-year-old woman with metastatic colorectal cancer whose bevacizumab (B-mab) +m-FOLFOX6 treatment was complicated by reversible posterior leukoencephalopathy syndrome (RPLS). In July 2011, she underwent a right hemicolectomy for cecal carcinoma with peritoneal dissemination; therefore, m-FOLFOX6 was started in September 2011. In November 2011, she was hospitalized to add B-mab to the existing regimen. Subsequently, she developed hypertension on day 4 after the first B-mab infusion, followed by headache, convulsions, and disturbance of consciousness on day 5. T2-weighted and fluid-attenuated inversion recovery (FLAIR) non-enhanced magnetic resonance imaging of the brain revealed bilateral high signal intensities in the posterior lobes. She was diagnosed with RPLS and referred to our department where she was treated with antihypertensives and anticonvulsives. Her symptoms entirely resolved over 12 days. Medical oncologists should be aware that multidrug chemotherapies with B-mab may increase the risk of fatal neurological complications such as RPLS.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Anticonvulsants; Antihypertensive Agents; Antineoplastic Combined Chemotherapy Protocols; Appendiceal Neoplasms; Bevacizumab; Colectomy; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Leukoencephalopathies; Magnetic Resonance Imaging; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

Chemotherapy is the principal treatment in metastatic colorectal cancer (mCRC) patients. RAC1b, a RAC1 spliced variant, is over-expressed in colorectal cancer (CRC), and impairs apoptosis by activation of nuclear-factor-KB. Since RAC1b has been associated with the BRAF(V600E) mutation, associated with poor prognosis in CRC, we evaluated the role of RAC1b expression as a predictor of chemotherapy efficacy in mCRC.. We analysed KRAS and BRAF mutation, microsatellite instability and RAC1b expression in 157 mCRC patients treated with FOLFOX/XELOX in first-line therapy.. KRAS mutations were detected in 46 patients (34%), 10 patients were BRAF mutant (7%) and 79 were WT for both, KRAS and BRAF (59%). RAC1b overexpression was found in 30 patients (19%). In the multivariate analysis, BRAF mutational status was a poor prognostic factor for overall survival (OS); hazard ratio (HR), 2.78 (95% confidence interval (CI), 1.35-5.72; p=0.0057). RAC1b overexpression was a poor survival factor for OS (HR, 2.35; 95% CI, 1.2-4.59; p=0.01) and progression-free survival (PFS) (HR, 2.4; 95% CI, 1.2-4.78; p=0.01) in KRAS/BRAF WT mCRC patients.. RAC1b overexpression constitutes a marker of poor prognosis in KRAS/BRAF WT mCRC patients treated with first-line FOLFOX/XELOX therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Genotype; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaloacetates; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); rac1 GTP-Binding Protein; ras Proteins

Neoadjuvant chemoradiotherapy is commonly used to improve the local control and resectability of locally advanced rectal cancer, with surgery performed after an interval of a number of weeks. We have been conducting a clinical trial of preoperative chemoradiotherapy in combination with regional hyperthermia (hyperthermo-chemoradiation therapy; HCRT) for locally advanced rectal cancer. In the current study we assessed the effect of a longer (>10 weeks) interval after neoadjuvant HCRT on pathological response, oncological outcome and especially on apoptosis, proliferation and p53 expression in patients with rectal cancer. Forty-eight patients with proven rectal adenocarcinoma who underwent HCRT followed by surgery were identified for inclusion in this study. Patients were divided into two groups according to the interval between HCRT and surgery, ≤ 10 weeks (short-interval group) and >10 weeks (long-interval group). Patients in the long-interval group had a significantly higher rate of pathological complete response (pCR) (43.5% vs. 16.0%) than patients of the short-interval group. Patients of the long-interval group had a significantly higher rate of down-staging of T-stage (78.3% vs. 36.0%) and relatively higher rate of that of N-stage (52.2% vs. 36.0%) than patients of the short-interval group. Furthermore, apoptosis in the long-interval group was relatively higher compared to that of the short-interval group, without a significant difference in the Ki-67 proliferative index and expression of p53 in the primary tumor. In conclusion, we demonstrated that a longer interval after HCRT (>10 weeks) seemed to result in a better chance of a pCR, a result confirmed by the trends in tumor response markers, including apoptosis, proliferation and p53 expression.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Chemoradiotherapy; Female; Fluorouracil; Humans; Hyperthermia, Induced; Immunoenzyme Techniques; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Rectal Neoplasms; Survival Rate; Treatment Outcome

FOLFOX second-line treatment seems to be a validated option for patients with pancreatic cancer (PC) progressing after gemcitabine chemotherapy. However, other therapeutics strategy has developed in first-line therapy, as the FIRGEM phase II study that evaluated gemcitabine alone versus FOLFIRI.3 alternating with gemcitabine every two months. The present study assessed the efficacy and safety of FOLFOX after failure of the first-line therapy used in the FIRGEM study.. In this prospective observational cohort study, we analysed all consecutive patients who received second-line chemotherapy with FOLFOX among 98 patients with metastatic PC included in the FIRGEM study. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method.. Among 46 patients who received second-line chemotherapy, 27 patients (male, 55%; median age, 61 years; performance status (PS) 0-1, 44%) were treated with FOLFOX after progression to first-line gemcitabine alone (n = 20) or FOLFIRI.3 alternating with gemcitabine (n = 7). Grade 3 toxicity was observed in 33% of patients (no grade 4 toxicity). At the end of follow-up, all patients had progressed and 25 had died. No objective response was observed, and disease control rate was 36%. Median PFS and OS were 1.7 and 4.3 months, respectively. In multivariate analysis, PS was the only independent prognostic factor. For patients PS 0-1 versus 2-3, median PFS was 3.0 versus 1.2 months (log rank, p = 0.002), and median OS was 5.9 versus 2.6 months (log rank, p = 0.001).. This study suggests that FOLFOX second-line therapy offered interesting efficacy results with an acceptable toxicity profile in metastatic PC patients with a good PS.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Pancreatic Neoplasms; Prognosis; Treatment Outcome

In 2008, the National Comprehensive Cancer Network guidelines were revised in light of the identification of the Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene as a biomarker of nonresponse to epidermal growth factor receptor inhibitors. This study sought to describe and compare real-world treatment patterns of metastatic colorectal cancer (mCRC) according to KRAS genotype in community-based oncology practices in the United States.. Data from the ACORN (ACORN LLC, Memphis, TN) electronic medical record data warehouse, containing data of approximately 180,000 patients from 12 oncology practices across the United States were used. Records of adult patients with mCRC who had undergone KRAS testing between January 2008 and December 2011 were evaluated. Patient demographic characteristics, KRAS genotype, and treatment patterns were identified and compared.. Six hundred forty-eight mCRC patients who were tested for KRAS were identified. Of these, 48.1% had wild type (WT), 42.3% mutant, and 9.6% unknown genotypes. Most patients (72.1%) were tested in 2009 or later, after the guideline revision. Bevacizumab-containing combinations were the most common first-line regimens in KRAS mutant and WT patients. Approximately 90% of patients received at least 1 line of therapy, however, WT patients received significantly more lines of therapy than KRAS mutant patients (2.6 ± 1.5 vs. 2.1 ± 1.2; P < .001).. KRAS WT and mutant genotypes had similar first-line regimens; however, WT patients received more lines of therapy. Although there does not appear to be a lag between changes in guidelines and treatment practice, professional and government organizations must keep up with the changing science and disseminate this information to oncologists in a timely manner.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Capecitabine; Cetuximab; Colorectal Neoplasms; Community Health Services; Deoxycytidine; ErbB Receptors; Female; Fluorouracil; Genotype; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Practice Guidelines as Topic; Practice Patterns, Physicians'; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; United States; Young Adult

The safety and efficacy of FOLFIRI as second-line chemotherapy for metastatic colorectal cancer patients ≥ 75 years was retrospectively evaluated. We analyzed 106 patients, who received FOLFIRI or a combination of FOLFIRI and bevacizumab following oxaliplatin-based first-line chemotherapy. The clinical characteristics and outcome in elderly patients ≥75 years(elderly[EP]group; n=18)were compared with those in patients aged<75 years(control group; n=88). The number of patients treated by a combination of FOLFIRI and bevacizumab in the EP group was lower than that in the control group (27.8% vs 55.7%; p=0.03). The comparison revealed no significant differences in response rate, progression-free survival, overall survival, and the frequency of overall adverse events after the start of second-line chemotherapy, although the frequency of anemia(Bgrade 3, p=0.07)and alopecia(grade 1/2, p=0.054)tended to be higher in the EP group than in the control group. Although this study retrospectively analyzed a limited number of patients, our results indicate that the safety and efficacy of FOLFIRI as second-line chemotherapy for metastatic colorectal cancer are almost equal in patients ≥ 75 years and those aged<75 years.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Retrospective Studies

To estimate the incremental cost per life-year gained (LYG) of aflibercept in combination with FOLFIRI as second-line treatment in metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin.. Based on clinical trial VELOUR results, a three-state Markov model (stable disease, progression and death) with 2-week cycle duration was designed. Transition to health state «progression» implied the interruption of second-line treatment and administration of a third-line treatment (post-second line chemotherapy). Cost estimation included disease management cost (pharmaceutical, adverse event management, administration costs, etc.). Both cost and outcomes were discounted (3% annually). Sensitivity analyses (SA) were performed to test model robustness.. Administration of aflibercept + FOLFIRI as second-line treatment provided 1.78 LYG (21 life-months gained). With FOLFIRI 1.43 LYG (17 months) were obtained. The cost of the clinical management of aflibercept + FOLFIRI implied an additional investment of Euros 13,564 compared with FOLFIRI for a lifetime horizon, being total costs for aflibercept + FOLFIRI of Euros 38,346, compared to Euros 24,782 with FOLFIRI. In the cost-effectiveness analysis Euros 38,931/LYG was obtained with aflibercept in combination with FOLFIRI versus FOLFIRI.. Aflibercept in combination with FOLFIRI increased overall survival versus FOLFIRI, so it is an effective strategy in the treatment of patients with mCRC. Aflibercept in combination with FOLFIRI is an efficient strategy for second-line mCRC treatment from the National Health System perspective.. Estimar el coste incremental por año de vida ganado (AVG) de la utilización de aflibercept en combinación con FOLFIRI como tratamiento de 2ª línea en pacientes con cáncer colorrectal metastásico (CCRm) previamente tratados con oxaliplatino. MATERIAL Y MÉTODOS: Basándose en los resultados del ensayo clínico VELOUR, se utilizó un modelo de Markov con 3 estados de salud (enfermedad estable, progresión y muerte) y ciclos de 2 semanas. La transición al estado de salud «progresión» implicaba interrumpir el tratamiento en 2ª línea y administrar una 3ª línea de tratamiento. La estimación de costes incluyó costes del manejo de la enfermedad (farmacológicos, acontecimientos adversos, administración, etc.). Costes y resultados en salud fueron descontados al 3% anualmente. Para probar la robustez del modelo se realizaron análisis de sensibilidad determinístico y probabilístico.. La administración de aflibercept + FOLFIRI como 2ª línea de quimioterapia aporta 1,78 AVG (21 meses de vida ganados). Con FOLFIRI se consiguen 1,43 AVG (17 meses). El coste del manejo clínico de aflibercept + FOLFIRI supone una inversión adicional de 13.564 frente a FOLFIRI a lo largo de toda la vida del paciente, siendo el coste total de 38.346 para aflibercept + FOLFIRI y 24.782 para FOLFIRI. Se obtiene un RCEI (ratio coste efectividad incremental) de 38.931 /AVG con aflibercept + FOLFIRI frente a FOLFIRI. CONCLUSIÓN: Aflibercept en combinación con FOLFIRI incrementa la supervivencia global frente a FOLFIRI, lo que supone una estrategia efectiva en el tratamiento de pacientes con CCRm. La relación coste-efectividad incremental de aflibercept en combinación con FOLFIRI supone una estrategia eficiente, coste-efectiva, para el Sistema Nacional de Salud.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Markov Chains; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

The VELOUR study demonstrated a survival benefit for FOLFIRI + aflibercept versus FOLFIRI + placebo in metastatic colorectal cancer (mCRC) patients who progressed on oxaliplatin-based chemotherapy. Continued divergence of overall survival (OS) curves in the intension to treat (ITT) population, with the survival advantage persisting beyond median survival time, suggested subpopulations might have different magnitudes of survival gain. Additionally, 10% of patients within VELOUR had recurrence during or within 6 months of completing oxaliplatin-based adjuvant therapy (adjuvant fast relapsers)--previously identified as having poorer survival outcomes.. To determine which patients received the greatest benefit from FOLFIRI-aflibercept, a post hoc multivariate analysis of the VELOUR ITT population was conducted. Prognostic factors identified were applied to the ITT population, excluding adjuvant fast relapsers, to derive OS prognostic profiles.. The better efficacy subgroup was identified as patients within VELOUR exclusive of adjuvant fast relapsers and had performance status (PS) 0 with any number of metastatic site or PS 1 with <2 metastatic site. A significant improvement in efficacy outcome was observed with aflibercept in the better efficacy subgroup. Median OS for FOLFIRI-aflibercept and FOLFIRI-placebo:16.2 and 13.1 months (adjusted Hazard Ratio [HR] = 0.73; 95% confidence interval [CI]: 0.61-0.86); median progression free survival (PFS): 7.2 and 4.8 months (adjusted HR = 0.68; 95% CI: 0.57-0.80); and objective response rate (ORR): 24% versus 11% respectively. Poorer efficacy subgroup comprised of adjuvant fast relapsers or patients with PS2 or PS1 with ≥ 2 metastatic sites. In poorer efficacy subgroup, no benefit was seen with aflibercept. Median OS for FOLFIRI-aflibercept and FOLFIRI-placebo: 10.4 and 9.6 months (adjusted HR = 0.97; 95% CI: 0.78-1.21) respectively with no improvement in PFS or ORR.. This analysis suggests that within VELOUR, patients in the better efficacy subgroup may derive enhanced benefit from treatment with FOLFIRI-aflibercept. These prognostic criteria may guide practitioners toward optimal use of targeted biologicals in appropriate second-line mCRC patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Survival Analysis; Treatment Outcome

To investigate the cost-effectiveness of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fluorouracil and leucovorin) compared with bevacizumab plus mFOLFOX6 in first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC).. A semi-Markov model was constructed from a French health collective perspective, with health states related to first-line treatment (progression-free), disease progression with and without subsequent active treatment, resection of metastases, disease-free after successful resection and death.. Parametric survival analyses of patient-level progression-free and overall survival data from the only head-to-head clinical trial of panitumumab and bevacizumab (PEAK) were performed to estimate transitions to disease progression and death. Additional data from PEAK informed the amount of each drug consumed, duration of therapy, subsequent therapy use, and toxicities related to mCRC treatment. Literature and French public data sources were used to estimate unit costs associated with treatment and duration of subsequent active therapies. Utility weights were calculated from patient-level data from panitumumab trials in the first-, second- and third-line settings. A life-time perspective was applied. Scenario, one-way, and probabilistic sensitivity analyses were performed.. Based on a head-to-head clinical trial that demonstrates better efficacy outcomes for patients with wild-type RAS mCRC who receive panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6, the incremental cost per life-year gained was estimated to be €26,918, and the incremental cost per quality-adjusted life year (QALY) gained was estimated to be €36,577. Sensitivity analyses indicate the model is robust to alternative parameters and assumptions.. The incremental cost per QALY gained indicates that panitumumab plus mFOLFOX6 represents good value for money in comparison to bevacizumab plus mFOLFOX6 and, with a willingness-to-pay ranging from €40,000 to €60,000, can be considered cost-effective in first-line treatment of patients with wild-type RAS mCRC.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Exons; Female; Fluorouracil; Health Care Costs; Humans; Leucovorin; Male; Markov Chains; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Panitumumab; Probability; Quality-Adjusted Life Years; ras Proteins; Treatment Outcome

We evaluated the relationship between carcinoembryonic antigen half-life (CEA-HL) in the early period of induction chemotherapy for patients with liver metastases from colorectal cancer (CRLM) and their clinicopathological response.. Seventy-four patients with initially unresectable CRLM received FOLFOX with or without bevacizumab and 30 patients underwent hepatic resection. The CEA-HL in the early postoperative period was investigated, and the pathological response was classified according to tumor regression grade (TRG).. The CEA-HL after the third chemotherapeutic course (CEA-HL3) was significantly shorter in responders compared to non-responders. In the 30 patients who underwent hepatectomy, the CEA-HL3 was significantly shorter in the major or complete-pathological-response group for the TRGs than in the the partial-pathological-response group. If the patients were divided into two groups according to the median value of 20 days, progression-free survival and overall survival were significantly better in those with CEA-HL3 below the cut-off.. The CEA-HL is an early predictor of the pathological response and prognosis after induction chemotherapy for CRLM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Colorectal Neoplasms; Female; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Treatment Outcome

Prognosis of metastatic breast cancer is poor with a 5-year survival rate of 21%. Even though it is incurable, the majority of patients needs a treatment to ameliorate symptoms and prolong survival. If chemotherapy is indicated, toxicity of multi-drug regimens often out-weighs the possible gain, making single-agent chemotherapy the preferred choice. Although capecitabine is frequently used for the treatment of metastatic breast cancer, it is not a therapeutic option for all patients.. Since simultaneous application of 5-fluorouracil (5-FU) and sodium folinate is a promising alternative treatment for certain patients, we reviewed the cases of 26 patients treated at our site.. Progression-free survival (PFS) was 8.6 months and overall survival (OS) was 18.5 months with a beneficial toxicity profile.. The efficacy of simultaneous high level 5-FU and sodium folinate is comparable to other frequently used single-agent chemotherapies, while the toxicity profile is favorable.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Middle Aged; Neoplasm Metastasis; Survival Rate; Vitamin B Complex

XELOX plus bevacizumab (XELOX-Bev) and FOLFIRI plus Bevacizumab (FOLFIRI - Bev) treatments are an effective strategies patients with metastatic colorectal cancer (mCRC).The aim of this study was to compare efficacy of first-line XELOX-Bev treatment vs FOLFIRI-Bev treatment for mCRC.. A total of 409 patients with mCRC who received chemotherapy were included and divided into 2 groups. Group 1 (n=298) received XELOX-Bev and Group 2 (n=111) FOLFIRI-Bev. Comparisons were made in terms of overall (OS) and progression-free (PFS) survival, response rate (RR), and grade 3-4 toxicity.. Median follow-up was 11 months in Group 1 and 15 months for Group 2. Complete remission was observed in 29 (9.7%) and 2 (1.8%) patients, partial remission in 139 (46.6%) and 27 (24.5%) , stable disease in 88 (29.5%) and 49 (44.1%) and progressive disease in 42 (14.1%) and 33 (30.0%) patients in Group 1 and 2, respectively. Median OS was 25 months (range 2-57 months, 95%CI; 22.2-27.7) for Group 1 and 20 months (range 1-67 months, 95%CI; 16.8-23.1) for Group 2 (p=0.036). Median PFS was 9.6 months (range 2-36 months, 95%CI; 8.8-10.4) for Group 1 and 9 months (range 1-44 months, 95%CI; 7.4-10.5) for Group 2 (p=0.019). Objective RR was 56.4% in Group 1 and 26.1% in Group 2 (p<0.001).. First-line XELOX-Bev is more effective with a better response rate, prolongation of median PFS/OS, and a superior safety profile compared with FOLFIRI-Bev.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Camptothecin; Capecitabine; Carcinoma; Colonic Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Oxaloacetates; Retrospective Studies; Treatment Outcome

Aflibercept, an intravenously administered anti-VEGF and antiplacental growth factor (PlGF) agent, has recently been approved by the U.S. Food and Drug Administration in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer who have previously received an oxaliplatin-containing chemotherapy regimen. In the phase III VELOUR trial, aflibercept plus FOLFIRI statistically significantly prolonged both progression-free survival (PFS; median PFS for the aflibercept plus FOLFIRI arm was 6.90 vs. 4.67 months for the placebo-plus-FOLFIRI arm) and overall survival (median overall survival for the aflibercept-plus-FOLFIRI arm was 13.50 vs. 12.06 months for the placebo plus FOLFIRI arm), but grade 3 or 4 adverse events were more common with the addition of aflibercept. However, the addition of aflibercept to 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in the phase II AFFIRM trial of first-line treatment of mCRC failed to improve PFS or response rate. As a decoy VEGF receptor, aflibercept (VEGF-Trap) has binding affinity for VEGF-A, VEGF-B, PlGF-1, and PlGF-2, and this is a mechanism of significant interest. Optimal strategies for incorporating aflibercept into treatment regimens that include other anti-VEGF and cytotoxic chemotherapeutic agents, as well as development of predictive biomarkers for treatment response, have yet to be defined.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Placenta Growth Factor; Pregnancy Proteins; Protein Binding; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor B

To identify changes in peripheral immune responses in patients with metastatic colorectal cancer (mCRC) treated with irinotecan/5-fluorouracil/leucovorin (IFL) alone or in combination with cetuximab (C-IFL).. Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (n = 20) and patients with mCRC receiving treatment with either IFL (n = 30) or C-IFL (n = 30) were tested for cytokine production upon polyclonal stimulation with anti-CD3 monoclonal antibody, T cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR) and T regulatory cell (Treg) frequency. The respective results were evaluated over two treatment cycles and further assessed in relation to response to treatment.. PBMCs prior to treatment exhibited significantly lower production of IL-2, IFN-γ, IL-12 and IL-18 cytokines and lower auto-MLR responses, whereas Treg frequency, IL-4, IL-10 cytokines were increased compared to healthy donors. During treatment, IL-2, IFN-γ, IL-12, IL-18 and auto-MLR responses increased, while Treg frequency and IL-10 secretion decreased significantly compared to the baseline. Responders to treatment exhibited a significantly higher increase in IL-2, IFN-γ, IL-12 and IL-18 production and auto-MLR responses, and higher decrease in IL-4, IL-10 secretion and Treg frequency. Among all patient subgroups analysed, responders to C-IFL demonstrated significantly higher increase in auto-MLR responses, IL-12 and IL-18 secretion and higher decrease in Treg frequency.. The disturbed immune parameters observed in patients with mCRC at presentation can be significantly improved during treatment with IFL and this effect can be potentiated by the addition of cetuximab. Monitoring of the peripheral immune system function could be used as surrogate marker in predicting treatment-related outcome.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; CD3 Complex; Cetuximab; Colorectal Neoplasms; Cytokines; Female; Fluorouracil; Humans; Leucovorin; Leukocytes, Mononuclear; Male; Middle Aged; Neoplasm Metastasis; Phenotype; T-Lymphocytes, Regulatory

Pancreatic cancer still remains a significant, unresolved therapeutic challenge and is the most lethal type of gastrointestinal cancer with a 5-year survival rate of 5%. Adjuvant chemotherapy remains to be gemcitabine alone, though fluorouracil offers the same survival and role of radiation remains controversial. Nevertheless, only a few patients survive for at least 5 years after R0 resection and adjuvant therapy. Borderline resectable pancreatic cancer remains an area that requires multi-disciplinary approach. Neo-adjuvant therapy very likely plays a role to downstage to a resectable state in these subgroup patients. There are different treatment approaches to locally advanced pancreatic cancer management, including single or multi-agent chemotherapy, chemotherapy followed by chemoradiation, or immediate concurrent chemoradiation. Most patients need palliative treatment. Once pancreatic cancer becomes metastatic, it is uniformly fatal with an overall survival of generally 6 months from time of diagnosis. Gemcitabine has been the standard since 1997. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, leucovorin) has already shown superiority over gemcitabine in both progression-free survival and overall survival, but this regimen is suitable only for selected patients in ECOG performance status 0-1. FOLFIRINOX has already trickled down to the clinic in various modifications and in different patient groups, both locally advanced and metastatic. Many targeted agents, including bevacizumab, cetuximab showed negative results, except mild benefit with addition of erlotinib with gemcitabine, which was not considered clinically significant. There is no consensus regarding treatment in the second-line setting. It will be true to say that there was a real medical breakthrough with regards to improving the prognosis of pancreatic cancer as of 2013 with the results of MPACT study. In this study, patients who received nab-paclitaxel plus gemcitabine lived a median of 8.5 months, compared with 6.7 months for those who received gemcitabine alone. At the end of one year, 35% of those getting nab-paclitaxel were alive, compared with 22% of those getting only gemcitabine. After two years, the figures were 9% for those getting nab-paclitaxel and 4% for those who received gemcitabine.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Models, Biological; Neoplasm Metastasis; Organoplatinum Compounds; Pancreatectomy; Pancreatic Neoplasms

We retrospectively analyzed ABCG2 expression levels in patients with metastatic colorectal cancer (CRC) to investigate the interaction between ABCG2 expression and the tumor response to oxaliplatin and 5-fluorouracil (FOLFOX).. Forty-three patients with CRC with liver metastasis who received first-line FOLFOX treatment at our institution between 2008 and 2010 were enrolled. ABCG2 expression was assessed by immunohistochemistry. Tumor response was determined using the modified Response Evaluation Criteria in Solid Tumors criteria.. At least 50% tumor shrinkage was observed in 16/43 patients (37.2%), including a complete response in 1 patient. According to the intensity of ABCG2 expression and the percentage of tumor cells expressing ABCG2, 21 tumors displayed high ABCG2 expression. Among these tumors, only 2 (9.5%) exhibited partial responses to FOLFOX; conversely, 63.6% of tumors with low ABCG2 expression (14/22) responded to FOLFOX. Primary and corresponding metastatic samples were available for 15 patients, and 13 of the metastatic tumors had higher ABCG2 expression than the corresponding primary tumors, but only 1 of these tumors responded to FOLFOX (7.7%).. ABCG2 expression is associated with the tumor response to FOLFOX in patients with metastatic CRC. ABCG2 may be a selective marker for the efficacy of FOLFOX in treating CRC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biomarkers, Pharmacological; Biomarkers, Tumor; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Organoplatinum Compounds; Paraffin Embedding; Prognosis

Oxaliplatin with 5-fluorouracil (5-FU) and leucovorin (FOLFOX and FLOX) or capecitabine (XELOX) is the standard adjuvant treatment for colonic cancer. In metastatic disease, 5-FU/leucovorin/irinotecan (FOLFIRI) and FOLFOX are equivalent in respect to response rates, progression-free and overall survival. Little data are available to compare their efficacy after exposure to oxaliplatin-containing adjuvant chemotherapy.. We carried out a retrospective study of patients who underwent surgery and FOLFOX adjuvant chemotherapy, followed by FOLFIRI or FOLFOX for metastatic disease. Exclusion criteria were: metastatic disease at presentation and no oxaliplatin in adjuvant chemotherapy. The end-point was the overall response rate (ORR) to first-line chemotherapy for metastatic disease after three months, as assessed by computed tomography (CT).. A total of 205 patients received FOLFOX as adjuvant treatment for colorectal adenocarcinoma between 2006 and 2010. Metastatic disease was diagnosed later in 32 cases after a median follow-up of three years (range=1-5.5 years). The median time between the beginning of adjuvant chemotherapy and onset of metastatic disease was 1.7 years (range=0.5-5.5 years). Twenty-eight patients were evaluable for effects of treatment: six patients received FOLFOX plus bevacizumab and 22 FOLFIRI plus bevacizumab. The ORR was 17% in the FOLFOX group versus 36% in the FOLFIRI group (p=0.22). This difference was not statistically significant, despite a trend in favor of FOLFIRI.. Metastatic disease after exposure to oxaliplatin in the adjuvant setting tends to occur early and can be characterized by partial resistance to this agent. Despite insufficient statistical power, our results suggest that FOLFIRI may result in higher response rates than FOLFOX in this situation. However, oxaliplatin re-challenge can also lead to radiological responses and disease stabilization.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate

We examined the whole genome expression profile in advanced colorectal cancer (ACC) patients who had received FOLFOX4 chemotherapy to establish a genetic biomarker model predicting chemotherapy sensitivity.. Eligible ACC patients were divided into two groups, based on postchemotherapy evaluation results: specifically, the sensitive group (experimental group) and the resistant group (control group). The genome expression profiles of colorectal cancer tissues were examined using DNA microarray analysis, and differential gene expression was identified using a significance analysis of the microarray. The probe signal log ratios were used to produce the area-under-the-curve, sensitivity, and specificity for candidate genes. Genes exhibiting differential expression and significant predictive power were used to simulate a genetic model for estimating chemotherapy sensitivity.. Totally, 30 ACC patients were eligible for the study, 13 assigned to the experimental group and 17 to the control group. In total, 30 genes showing significant differential expression were identified. Seven candidate genes (NKX2-3, FXYD6, TGFB1I1, ACTG2, ANPEP, HOXB8, and KLK11), which exhibited positive or negative correlations, were incorporated into a genetic model, with an overall accurate predication rate of 93.3%.. The predictive model involving the seven genes listed had high accuracy in estimating chemotherapy sensitivity to the FOLFOX4 regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression Profiling; Humans; Leucovorin; Liver Neoplasms; Male; Microarray Analysis; Middle Aged; Models, Genetic; Neoplasm Metastasis; Organoplatinum Compounds

Here we bioengineered a metastatic pancreatic tumor model with homogenous human CD133(+)CXCR4(+) cancer stem cells (CSC) and a polyglyconate/gelatin electrospun scaffold. The scaffold sported a highly porous microstructure with the majority of fibers possessing a diameter between 500μm and 1500μm. The scaffold supported the growth of tumor cells without provoking apoptosis. The homogeneous CD133(+)CXCR4(+) CSC was transplanted with the scaffold into the pancreas of nude mice to establish a metastatic pancreatic tumor. After 8 weeks, the tumor volume and weight in the scaffold model were 40.52% and 51.49% greater than the traditional model, respectively. The scaffold also increased the incidence of tumor formation and readily induced a hepatic metastasis. In this model we found that FOLFIRINOX possessed a superior capability of preventing the hepatic metastasis of pancreatic tumor cells than gemcitabine. A mechanistic study attributed this superiority to the fact that FOLFIRINOX could induce a greater apoptosis of CD133(+)CXCR4(+) CSC, thus depriving the driving force of hepatic metastasis. This metastatic tumor model showed an increased incidence of tumor formation, an accelerated tumorigenesis and a significant hepatic metastasis, therefore offering scientists a proven platform to study chemotherapeutic drugs.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bioengineering; Camptothecin; Cell Line, Tumor; Deoxycytidine; Disease Models, Animal; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Organoplatinum Compounds; Pancreatic Neoplasms; Tissue Scaffolds; Xenograft Model Antitumor Assays

Colorectal cancer patients with BRAF-mutant tumors have a more aggressive, rapidly progressing disease that is in critical need of novel therapeutic approaches. Indeed, whereas the median overall survival (OS) of colorectal cancer (CRC) patients receiving standard-of-care therapy is approximately two years or more if their tumors express wild-type BRAF and wild-type KRAS, median OS is less than twelve months with tumors expressing V600E-mutant BRAF and wild-type KRAS. Pro-apoptotic receptor agonists are a class of biologic agents under development to induce tumor-specific apoptosis and are being combined with classical chemotherapy or targeted agents in clinical trials. Herein, we present the case of a patient with bulky V600E-mutant BRAF hepatic flexure colon carcinoma, treated initially with FOLFOX plus bevacizumab neoadjuvant therapy and surgery. The patient had a rapid tumor relapse with metastatic disease to the liver and lung, and was enrolled in a phase 1b open-label clinical study, where he received the FOLFIRI regimen in combination with the pro-apoptotic receptor agonist dulanermin (rhApo2L/TRAIL). The patient maintained stable disease through 25 doses administered every two weeks before his disease progressed. After coming off study, the patient underwent surgical debulking and received intraperitoneal hyperthermic chemotherapy. He subsequently relapsed and was treated with FOLFIRI plus cetuximab. At the time of this report, the patient remains on active treatment. It is unclear what effect dulanermin may have had on the course of his disease, but it is noteworthy that the patient remained on FOLFIRI plus dulanermin therapy for a period that exceeded the median OS for patients with advanced, aggressive BRAF-mutant CRC. It is also noteworthy that at the time of this report the patient's overall survival since diagnosis has exceeded 30 months, which is beyond what is generally observed even for patients with CRC harboring wild-type BRAF and wild-type KRAS.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Proto-Oncogene Proteins B-raf; TNF-Related Apoptosis-Inducing Ligand

The KRAS oncogene is mutated in 40‒50% of colorectal cancers and confers resistance to EGFR-targeted therapy. In the clinic, agents such as cetuximab or panitumumab target the EGFR receptor for therapeutic benefit. Cetuximab was approved by the FDA in 2012 as first-line therapy for KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer, in combination with FOLFIRI (5-fluorouracil, irinotecan, leucovorin). Herein we report a case of metastatic colon cancer with conflicting testing results for the KRAS oncogene from two different reference laboratories. The discordant reports complicated the decision-making process regarding the administration of targeted anti-EGFR personalized therapy. As the second test result was wild-type from the same original pathological specimen, the patient was treated with cetuximab-containing combination chemotherapy and appeared to have a response after prior disease progression. It is unclear whether the observed response was fully due to regression of wild-type KRAS-containing tumor or any component of antibody-dependent cellular cytotoxicity to a heterogeneous tumor in this patient.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mutation; Neoplasm Metastasis; Precision Medicine; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins

Topics: Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Choriocarcinoma; Dactinomycin; Doxorubicin; Etoposide; Female; Humans; Leucovorin; Methotrexate; Neoplasm Metastasis; Pregnancy; Uterine Neoplasms; Vincristine

The potential impact of different SNPs of VEGF/VEGFR pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of VEGFA rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of VEGF/VEGFR pathway genes was included.. To detect a HR for PFS of 1.7 for VEGFA rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and β = 0.20, 199 events were required. VEGFA rs699946 A/G, rs699947 A/C, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS1 rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing.. Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to VEGFA rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05-1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95-1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082-1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14).. This prospective experience failed to validate the hypothesized predictive impact of VEGFA rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Therapy, Combination; Fluorouracil; Gene Expression; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neovascularization, Pathologic; Polymorphism, Single Nucleotide; Retrospective Studies; Sequence Analysis, DNA; Survival Analysis; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

The efficacy and safety of bevacizumab(BV), combined with infusional 5-fluorouracil/leucovorin(5-FU/LV)plus irinotecan(FOLFIRI)as the second-line treatment for metastatic colorectal cancer(mCRC)after resection of the primary lesion, have not been fully clarified. We examined clinical results of 35 patients on BV plus FOLFIRI at our hospital, and investigated the efficacy of BV plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens(26 patients were treated with BV at a dose of 5mg/kg, 3 patients with BV 10mg/kg, and 6 patients had BV increased from 5mg/kg to 10mg/kg). The average frequency of BV plus FOLFIRI treatment was 13. 9 times, and the average length of treatment was 10. 0 months. The overall response rate was 17. 1%(CR 1 patient, PR 5 patients, SD 21 patients, PD 8 patients). The median PFS was 11. 0 months for FOLFIRI plus BV after first-line chemotherapy, and the median OS was 23. 0 months. The adverse events were 77. 1%(>Grade 3, 55. 5%)and the BV-associated adverse event was grade 3 hypertension(2 patients). The FOLFIRI plus BV regimen is an active and well-tolerated second-line chemotherapy treatment for patients with mCRC after resection of the primary lesion.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

The aim of this retrospective study was to show the efficacy and safety of modified FOLFOX6 plus high-dose bevacizumab (10 mg/kg/2 weeks) in the second-line or later treatment of metastatic colorectal cancer.. A total of 24 consecutive patients treated between August 2007 and August 2009 were included in this retrospective study. None of the patients had received bevacizumab as part of prior treatment.. All 24 patients received modified FOLFOX6 plus high-dose bevacizumab and were followed for a median of 36.9 months. Overall response rate was 29%. Median progression-free survival was 7.5 months, and median overall survival was 17.3 months. Grade 3/4 adverse events were: neutropenia (54.2%), leukopenia (25.0%), neuropathy (12.5%), hypertension (12.5%), thrombocytopenia (8.3%), and decreased haemoglobin, gastrointestinal haemorrhage, wound complications, nausea, diarrhoea, mucositis and fatigue (each 4.2%).. Modified FOLFOX6 plus high-dose bevacizumab may be useful in the second-line treatment of patients with metastatic colorectal cancer who have not received bevacizumab.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Mucositis; Nausea; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Young Adult

Membrane transporters are widely recognized as important determinants of drug disposition and response, generating increasing interest on the pharmacological implications of their genetic variations. The aim of this study was to elucidate the predictive/prognostic role of ATP-binding cassette (ABC) and solute carrier (SLC) protein polymorphisms on irinotecan (FOLFIRI regimen) outcome.. A total of 250 White metastatic colorectal cancer patients homogenously treated with a first-line FOLFIRI regimen were genotyped for a panel of variants in five transporter genes. The primary study endpoints were the response rate (partial or complete response), overall survival, and time to progression. Toxicity was considered a secondary endpoint. Irinotecan pharmacokinetic data of 71 patients were used for polymorphism functional analysis.. Two variants of the ABCG2 (-15622C>T, rs7699188) gene were found to be predictive (P < 0.01) of the response rate. High-order relationships of ABC/SLC markers with previously investigated genetic (UGT1A1 polymorphisms) and nongenetic (primary tumor site) factors that helped determine the response rate were highlighted. A prognostic effect of the ABCB1 rs2032582 variant on patient overall survival emerged (P = 0.0074). The ABCG2 rs7699788 variant was also seen to be associated with grade 3-4 nonhematological toxicity (P = 0.0012). The ABCG2 (-15622C>T, rs7699188) and ABCB1 (rs2032582) polymorphisms were not found to be associated with pharmacokinetic parameters.. This study showed that ABC/SLC polymorphisms have a crucial contribution toward the FOLFIRI outcome. This could represent a further step toward personalized therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; ATP-Binding Cassette Transporters; Camptothecin; Colorectal Neoplasms; Fluorouracil; Genetic Variation; Genotype; Humans; Irinotecan; Leucovorin; Linkage Disequilibrium; Liver-Specific Organic Anion Transporter 1; Neoplasm Metastasis; Organic Anion Transporters; Pharmacogenetics; Polymorphism, Single Nucleotide; Treatment Outcome

To evaluate the tolerability and efficacy of oxaliplatin-based chemotherapy (OBC) in patients ≥ 75 years old with metastatic colorectal cancer (CRC).. We reviewed the medical records of 126 patients with unresectable stage IV CRC in terms of OBC administered as first-line chemotherapy whenever feasible.. Use of first-line OBC was significantly less frequent in patients ≥ 75 years old (n=18) than in patients <75 years old (n=108) (46% vs. 81% p<0.01). When analysis was restricted to patients receiving OBC, the two age groups did not differ significantly in terms of response rate (44% vs. 36%, p=0.54), progression-free survival (18.7 months vs. 13.0 months, p=0.44), overall survival (25.4 months vs. 17.5 months, p=0.53), and frequency of grade 3-4 toxicity (72% vs. 58%, p=0.26).. In selected patients aged 75 years or greater, the clinical outcomes of OBC seem equivalent to those of younger patients.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Induction Chemotherapy; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Treatment Outcome

The aim of this study was to evaluate the efficacy and tolerability of a gemcitabine, 5-fluorouracil and leucovorin (GEMFUFOL) chemotherapy regimen as first line treatment of metastatic biliary tract cancer.. All patients received folinic acid 400 mg/m(2) on day 1, 5-fluorouracil bolus 400 mg/ m2 on day 1, IV infusion of 5-fluorouracil 2400 mg/m(2) over 46 hours, and gemcitabine 1250 mg/m(2) on day 1.. A total of 29 patients with metastatic biliary tract cancer received GEMFUFOL regimen as the first- line treatment. The mean follow-up was 22.1 months (95%CI, 12.5-31.8). One patient (3.4%) achieved complete response, 5 (17.2%) had partial response, and 4 (13.8%) had stable disease. The median progression-free survival was 3.3 months (95%CI, 2.9-3.7), and the median overall survival was 8.8 months (95%CI, 3.5-14). The 1-year and 2-year survival rates were 58.6% and 30%, respectively. Grade 3 and 4 toxicity included neutropenia in 4 patients (13.7%), thrombocytopenia in 2 (6.8%), anemia in 2 (6.8%), and alopecia in 1 (3.4%). Two patients (6.8%) developed febrile neutropenia. A dose reduction was achieved in 8 patients (27.6%) while 5 patients had extended-interval dosage (17.2%) for toxicity.. The GEMFUFOL chemotherapy regimen was generally efficacious and tolerable as a first-line treatment of metastatic biliary tract cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Rate

To determine the clinical significance of C-reactive protein (CRP) concentration in patients with stage IV colorectal cancer (CRC) undergoing oxaliplatin-based chemotherapy.. We retrospectively reviewed the medical charts of 112 patients with stage IV CRC who had received modified FOLFOX6 (5-fluorouracil, oxaliplatin, leucovorin) between January 2006, and December 2010 and used Cox's proportional hazard model to determine for independent prognostic factors of survival. We generated receiver operating characteristics (ROC) curves to determine the optimal cut-off for the discrimination of the duration of survival by CRP concentration.. According to the multivariate analysis, increased CRP concentration (p=0.04) and non-curative surgery (p<0.01) were independent unfavorable factors for survival, and the optimal cut-off CRP concentration according to dichotomized duration of survival (3-24 months) ranged from 0.8 to 1.2 mg/dl.. Pre-chemotherapy CRP concentrations may be useful for predicting survival of patients with stage IV CRC.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; C-Reactive Protein; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; ROC Curve; Survival Rate

The purpose of this study was to investigate the value of postoperative chemotherapy for locally advanced rectal cancer patients who reached pathological ypT1-4N0 after neo-adjuvant chemoradiotherapy.. We performed a retrospective study of 104 patients treated with preoperative chemoradiotherapy followed by radical resection, who achieved pathological ypT1-4N0, between Mar 2003 and Dec 2010. There were 73 patients who received postoperative adjuvant chemotherapy, and the other 31 patients did not. The distribution of final pathologic stages for these patients was ypT1-2N0 in 39 cases and ypT3-4N0 in 65 cases.. The median follow-up was 41 months. The 3-year overall survival rate (OS) and recurrence-free survival rate (RFS) for the whole group (ypT1-4N0) were 93.4% and 85.3%, respectively. The 3-year OS and RFS in the adjuvant chemotherapy group and non-adjuvant chemotherapy group were 95.5%, 88.6% and 88.6%, 77.2%, respectively. There were no significant differences in 3-year RFS (P = 0.108) and OS (P = 0.106) between the two groups. The 3-year local recurrence and distant metastasis rates in the adjuvant chemotherapy group were 4.1% (3/73) and 5.5% (4/73), while for the non-adjuvant chemotherapy group, the 3-year local recurrence rate and distant metastasis rate were 3.2% (1/31) and 16.1% (5/31), respectively. Significant difference was found in distant metastasis rates (P = 0.030) between the two groups, but not in local recurrence rates (P = 0.676).Further subgroup analysis indicated that for the ypT1-2N0 patients, there were no significant differences in 3-year OS (P = 0.296) and RFS (P = 0.939) between the adjuvant and non-adjuvant chemotherapy groups, while negative results displayed in 3-year local recurrence rates (P = 0.676) and distant metastasis rates (P = 0.414). However, for patients with ypT3-4N0, significant differences were showed in both the 3-year OS (P = 0.034) and RFS (P = 0.025), and further analysis revealed that the 3-year distant metastasis rate was significantly higher in the non-adjuvant chemotherapy group than in the adjuvant chemotherapy group (P = 0.010) , but with non-significant difference in the 3-year local recurrence (P = 0.548).. Adjuvant chemotherapy may not improve survival for ypT1-2N0 patients. However, it may be clinically meaningful for ypT3-4N0 patients by decreasing distant metastasis rate. Further randomized controlled clinical trials are needed to confirm our results.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Postoperative Period; Radiotherapy, Conformal; Rectal Neoplasms; Retrospective Studies; Survival Rate; Young Adult

In patients undergoing FOLFOX6 therapy for the treatment of unresectable/recurrent colorectal cancer, control of cumulative peripheral neuropathy is problematic. In our department, we stop using mFOLFOX6 as a primary therapy after 6 to 8 courses. Instead, we use mFOLFOX6 as a secondary therapy, and re-introduce mFOLFOX6 as a tertiary therapy; the patients undergoing this treatment protocol were included in Group A. We have studied the degree of neurotoxicity and the time of its occurrence in these patients compared to those undergoing the standard method (Group B; 12 cases). Grade 3 peripheral neuropathy was observed in both the groups. In Group B, peripheral neuropathy occurred in the primary treatment period, whereas in Group A, it appeared in the tertiary treatment period. Moreover, in Group A, we observed Grade 2 peripheral neuropathy in the primary treatment period in 3 cases, but this was promptly resolved after the therapy was shifted to the secondary treatment period. The period with neurological toxicities was shorter in Group A compared to Group B. When treating colorectal cancer with chemotherapy, it is important to elucidate how the prognosis can be improved while maintaining the quality of life( QOL). In our department, we place a greater emphasis on the QOL of the patient.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Quality of Life; Recurrence

An oxaliplatin-based regimen as the adjuvant treatment for stage III colon cancer demonstrated a survival advantage over fluorouracil (FU) and leucovorin (LV) in the MOSAIC and NSABP C-07 trials. For adjuvant treatment after the resection of metastases from colorectal cancer), active chemotherapy regimens such as FOLFOX are recommended. However, the safety data of FOLFOX are insufficient for its use after metastasectomy of colorectal cancer in Japanese patients. The aim of this study was to evaluate the safety of mFOLFOX6 for adjuvant treatment after the resection of metastases from colorectal cancer.. Among 67 consecutive patients who received mFOLFOX6 as the adjuvant treatment after resection of metastases from colorectal cancer between September 2002 and March 2009 in our institution, 51 patients who had not received preoperative chemotherapy were reviewed. The mFOLFOX6 treatment comprised oxaliplatin 85 mg/m(2) and l-leucovorin 200 mg/m(2) given intravenously over a 2-h period on day 1, followed by a 5-FU bolus of 400 mg/m(2) and a 46-h infusion of 5-FU 2400 mg/m(2), every 2 weeks for up to 12 cycles.. National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI-CTC) grade 3-4 toxicities per patient were: peripheral neuropathy 8%, allergic reaction 4%, aspartate transaminase (AST) 4%, febrile neutropenia 4%, nausea 2%, anorexia 2%, fatigue 2%, alanine transaminase (ALT) 2%, bilirubin 2%, neutrophils 49%, leukocytes 6%, and hemoglobin 2%; 71% of the patients completed the scheduled 12 cycles.. Adjuvant therapy with mFOLFOX6 after resection of metastases from colorectal cancer is feasible for Japanese patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

The role of d,l-leucovorin (d,l-LV) dose on efficacy and toxicity of first-line bevacizumab+mFOLFIRI or mFOLFIRI treatment has never been investigated in patients with metastatic colorectal cancer. This study was an investigator initiated retrospective observational investigation performed on 450 consecutive patients. The mFOLFIRI regimen consisted of irinotecan (180 mg/m(2)), d,l-LV low (200 mg/m(2)) or high (400 mg/m(2)) dose and bolus 5-fluorouracil (5-FU) (400 mg/m(2)), followed by a 46-h infusion of 5-FU (2400 mg/m(2)). The bevacizumab+mFOLFIRI regimen consisted of bevacizumab (5 mg/kg)+mFOLFIRI. The efficacy (objective response [OR], progression-free [PFS] and overall survival [OS]) and toxicity was evaluated and compared. The use of high versus low dose d,l-LV in bevacizumab+mFOLFIRI regimen improved the OR rate (63 and 38 %, respectively; P = 0.00015), median PFS (13 and 9 months, respectively; P = 0.000005) and median OS (26 and 21 months, respectively; P = 0.0058). The efficacy of mFOLFIRI and the toxicity pattern of both bevacizumab+mFOLFIRI and mFOLFIRI regimens were independent of d,l-LV dose. Beside the d,l-LV dose the bevacizumab-related hypertension was an independent marker of longer survival. The use of high d,l-LV dose in bevacizumab+mFOLFIRI regimen would enhance the antiangiogenic effect of bevacizumab and subsequently the efficacy of treatment without increasing the number of adverse events. These findings need to be further confirmed in a randomized controlled prospective trial.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Proportional Hazards Models; Retrospective Studies; Treatment Outcome

Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has showed clinical benefits in patients with metastatic colorectal cancer. Periodontitis has been observed infrequently in bevacizumab-containing chemotherapy in clinical practice. The purpose of this study was to retrospectively investigate bevacizumab-related periodontitis in metastatic colorectal cancer patients.. From January 2008 to March 2010, 274 patients received bevacizumab-containing chemotherapy at the National Cancer Center Hospital in Tokyo. Patients who had consulted the dentist for periodontitis were included in the study. We examined the interval between the initiation of the first bevacizumab administration and the day of the consultation with the dentist. Periodontitis was evaluated before and after conservative therapy.. Twenty-six patients (9.5 % of the 274 metastatic colorectal cancer patients) were included in this study. The median age was 60 years (range 30-79 years). Nineteen (73 %) patients had a good performance status of 0. The combination regimens used with bevacizumab were infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX, 53 %); infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI, 27 %); capecitabine + oxaliplatin (CapeOX, 8 %); S-1 + oxaliplatin (8 %); and S-1 + irinotecan (4 %). The median time from bevacizumab administration to the consultation with a dentist for periodontitis was 69 days (range 12-390 days), and the median number of bevacizumab administrations was 3.5 (range 1-25). After conservative therapy, 22 (85 %) patients with periodontitis showed an improvement.. Periodontitis occurred frequently in patients receiving bevacizumab. The conservative therapy for periodontitis was very effective, and the prophylaxitic treatment was important.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Periodontitis; Prednisone; Retrospective Studies; Treatment Outcome; Vindesine

Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated significant improvements in progression-free survival (PFS) in patients with wild-type KRAS metastatic colorectal cancer (mCRC) in studies 20050203 (first line), 20050181 (second line), and 20020408 (monotherapy). Mutations in KRAS codons 12 and 13 are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis of three randomized phase III studies assessed the prognostic and predictive impact of individual mutant KRAS codon 12 and 13 alleles.. Patients were randomly assigned 1:1 to FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) in study 20050203, FOLFIRI (fluorouracil, leucovorin, and irinotecan) in study 20050181, or best supportive care in study 20020408 with or without panitumumab 6.0 mg/kg once every 2 weeks. In all, 441 (20050203), 486 (20050181), and 126 (20020408) patients with mutant KRAS codon 12 or 13 alleles were included in the analysis.. No mutant KRAS allele in patients treated on the control arm emerged as a consistent prognostic factor for PFS or overall survival (OS). In addition, no mutant KRAS allele was consistently identified as a predictive factor for PFS or OS in patients receiving panitumumab treatment. Significant interactions for individual mutant KRAS alleles were observed only in study 20050203 with G13D negatively and G12V positively associated with OS in the panitumumab-containing arm. Pooled analysis indicated that only G12A was associated with a negative predictive effect on OS.. In this retrospective analysis, results across three treatment regimens suggest that patients with mutant KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Currently, panitumumab therapy should be limited to patients with wild-type KRAS mCRC.

Topics: Alleles; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Codon; Colorectal Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Gene Frequency; Humans; Irinotecan; Leucovorin; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Outcome Assessment, Health Care; Oxaliplatin; Panitumumab; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Randomized Controlled Trials as Topic; ras Proteins; Retrospective Studies; Survival Analysis

The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival.. Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (200 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 600 mg/m(2) in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (400 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 2400 mg/m(2) in a 46-h continuous infusion) on day 1.. A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7-2.5] and 5.6 months (95 % CI, 4.7-6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS.. The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Carcinoma, Signet Ring Cell; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Platinum; Retrospective Studies; Salvage Therapy; Stomach Neoplasms; Survival Rate; Taxoids; Treatment Outcome

Combination chemotherapies of oxaliplatin or irinotecan with fluoropyrimidine and molecular target drug were reported to be active in several clinical studies and so regarded as a first-line standard therapy for unresectable or metastatic colorectal cancer. However, the incidence of adverse events is not so low. We investigated the efficacy and safety of chemotherapy combined bevacizumab with fluoropyrimidine as a first-line treatment for frail patients.. Twenty-six patients with unresectable or metastatic colorectal cancer who were treated with first-line chemotherapy combined bevacizumab with S-1 or 5FU/LV (modified Roswell Park Memorial Institute regimen) at our hospital between October 2007 and December 2010 were retrospectively investigated.. The median age was 72 years (range 66-84). Performance status was 0, 1 and 2 in 8, 17 and 1 patient, respectively. The primary lesion was located in the colon in 14 patients and in the rectum in 12. Twenty patients were with resection of the primary lesion and 6 were without, 8 were with postoperative adjuvant chemotherapy and 18 were without. The number of metastasized organs was 1, 2 and 3 in 17, 9 and 0 patients, respectively. The liver, lung, lymph node and peritoneum were metastasized in 9, 9, 11 and 5 patients, respectively. The KRAS gene was wild in 11, mutated in 7 and unknown in 8 patients. Bevacizumab with S-1 was used in 17 patients and bevacizumab with 5FU/LV was used in 9. Response and disease control rates were 50 and 100%, respectively. The median duration of progression-free survival was 9.1 months and the median time to treatment failure was 9.0 months. The incidences of all grades of neutropenia and hypertension were 31%, those of grade 3 or severer were 12%, and those of other adverse events were low. Grade 3 cerebral hemorrhage, grade 4 pulmonary embolism and grade 5 febrile neutropenia each occurred in 1 patient.. The first-line chemotherapy combined bevacizumab with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer in Japan was comparable to the safety and efficacy of combination therapy reported previously in Western countries.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Frail Elderly; Humans; Leucovorin; Male; Neoplasm Metastasis; Oxonic Acid; Retrospective Studies; Tegafur; Treatment Failure; Vascular Endothelial Growth Factor A

The aim of this study was to determine the pathological complete remission (pCR) rate, and its relationship to clinical outcome, in patients with adenocarcinoma of the stomach or oesophagogastric junction receiving preoperative 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) every 2 weeks. Data from these patients who received at least one cycle of preoperative FLOT followed by surgery were prospectively collected in three German centres. Outcome analyses were conducted and tumour samples were evaluated for pathological remission by a central pathologist. A total of 46 patients were included in this analysis. All patients had clinical T3- and/or N+-stages and 11 (23.9%) had distant metastases (M1). After a median of 4 (range 2-8) preoperative cycles, 8 of 46 patients (17.4%) achieved a pCR. The pCR rate was highest in tumours of intestinal type histology (30.8%) and in those located in the oesophagogastric junction (30.4%) and lowest in patients with diffuse/mixed type tumours (0%) or tumours located in the stomach (4.3%; p < 0.05 for both comparisons). Patients with pCR had 100% probability of overall and disease-free survival (DFS) during the observation period, which was significantly higher (p = 0.037 and p = 0.009, respectively) than the survival probability in patients without pCR. In conclusion, treatment intensification using FLOT was associated with significant pCR rates in patients with oesophagogastric cancer. The distribution of pCR appeared to be significantly different according to histological type and location of the tumours.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Esophageal Neoplasms; Esophagogastric Junction; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Remission Induction; Stomach Neoplasms; Taxoids; Treatment Outcome

To validate established cutoff levels of thymidylate synthase (TS) and excision repair cross-complementing (ERCC-1) intratumoral mRNA expressions in tumor samples from metastatic colorectal cancer (mCRC) patients treated with PTK787/ZK222584 (PTK/ZK). From 122 samples of patients with mCRC enrolled in CONFIRM-1 (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases) or CONFIRM-2, mRNA was isolated of microdissected formalin-fixed paraffin-embedded samples and quantitated using TaqMan-based technology. Existing TS and ERCC-1 cutoff levels were tested for their prognostic value in first-line and second-line therapy. TS expression was associated with overall survival (OS) in first-line, but not second-line therapy. ERCC-1 was associated with OS in patients treated with first-line and second-line FOLFOX4. In first-line FOLFOX4, combination of high TS and/or high ERCC-1 was associated with shorter OS. A correlation was observed between ERCC-1 expression and benefit from PTK/ZK+FOLFOX4 treatment. TS and ERCC-1 expression is associated with clinical outcome in mCRC. Baseline TS and ERCC-1 levels may allow the selection of patients who benefit from FOLFOX4 chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; RNA, Messenger; Survival Analysis; Thymidylate Synthase; Treatment Outcome

Several oxaliplatin-specific scales have been proposed in clinical practice to evaluate oxaliplatin-related neurotoxicity. We investigated whether there might be a discrepancy between the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) and the Neurotoxicity Criteria of Debiopharm (DEB-NTC), the commonly used oxaliplatin-specific scales, in the evaluation of peripheral neurotoxicity.. The subjects were 42 patients with metastatic colorectal cancer who received more than 6 cycles of first-line therapy with modified FOLFOX6 and more than 6 cycles of second-line therapy with FOLFIRI. The median number and cumulative dose of oxaliplatin administrations were 10.5 (range 6-22) and 889.4 mg/m(2) (range 484.5-1875.0 mg/m(2)), respectively. The peripheral neurotoxicity was evaluated during mFOLFOX6 therapy and after its discontinuation using NCI-CTCAE ver. 3.0 and DEB-NTC. Data were collected prospectively and analyzed retrospectively.. The concordance rate of the peripheral neurotoxicity grade determined by these criteria was low: 48.8% during mFOLFOX6 and 47.3% after discontinuation of therapy. The cumulative dose of oxaliplatin-related peripheral neurotoxicity in 50% of the patients was lower when evaluated by DEB-NTC for both grades 1 (P = 0.09) and 2 (P < 0.001). The cumulative rate of improvement from grade 2 to 1 (P < 0.001) and from grade 2 to 0 (P < 0.05) after discontinuation of mFOLFOX6 therapy was higher when NCI-CTCAE was used for the evaluation.. We found a discrepancy between the NCI-CTCAE and DEB-NTC scales in the evaluation of oxaliplatin-related neurotoxicity and suggest that the concomitant use of NCI-CTCAE and DEB-NTC would be useful to maintain oxaliplatin-based chemotherapy at higher quality.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; National Cancer Institute (U.S.); Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Reference Standards; United States

Despite therapeutic innovations, metastatic colorectal cancer (mCRC) is still characterized by poor prognosis and few molecular markers predict the risk of progression. Polycomb group genes (PcGs) are epigenetic modifiers involved in tumor suppressor gene silencing. PcG member EZH2 mediates gene silencing through histone-H3 lysine-27 methylation. In colorectal cancer (CRC), EZH2 overexpression predicts shorter survival. Recently, four EZH2 single-nucleotide polymorphisms (SNPs) have been described. The present study was aimed at evaluating the correlation between EZH2 SNPs and outcome parameters in mCRC patients.. DNA was extracted from blood samples of 110 mCRC patients treated with first-line 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) and bevacizumab. Genotyping was carried out by real-time PCR. Genotype was used to predict objective response, progression-free survival (PFS) and overall survival (OS). EZH2 messenger RNA levels were evaluated on lymphocytes of a parallel cohort of 50 CRC patients.. One allelic variant (rs3757441 C/C versus C/T or T/T) was significantly associated with shorter PFS and OS (P < 0.01 and P < 0.05, respectively). At multivariate analysis, the same variant resulted an independent predictor of PFS and OS (P < 0.05). The C/C variant was associated with significantly higher EZH2 expression (P < 0.05).. An EZH2 SNP may be useful to predict clinical outcome in mCRC patients.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Female; Fluorouracil; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Polycomb Repressive Complex 2; Polymorphism, Single Nucleotide; Prognosis; Retrospective Studies; Transcription Factors; Treatment Outcome

The risks of chemoradiotherapy in elderly patients with rectal cancer have not yet been well-characterised.. We retrospectively reviewed the charts of patients with rectal cancer over 70 years old who were treated with chemoradiotherapy in two French university hospitals.. A total of 125 patients were evaluated. Mean age was 75.1 ± 4.1 years and ranged from 70 to 90 years. Adverse effects ≥ grade 2 were observed in 32% of the patients and adverse effects ≥ grade 3 in 15%. Dose reduction for toxicity was performed in 18% of the patients and chemoradiotherapy discontinuation was necessary in 9%. Postoperative morbidity was 16% with two treatment-related deaths. Two-year survival rate was 84%. No variables had any influence on treatment-related adverse events.. In selected elderly patients, chemoradiotherapy is well-tolerated, without any significant increase in adverse events, and the results are similar to those recorded in younger patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Capecitabine; Chemoradiotherapy, Adjuvant; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; France; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Retrospective Studies; Tegafur; Vitamin B Complex

Treatment outcomes improved in metastatic colorectal cancer (mCRC) due to the introduction of new chemotherapies and monoclonal antibodies. This study describes current patterns of pharmacological treatment for mCRC in clinical practice in four European countries.. This cohort study used physician-survey data from the LifeLink Oncology Analyzer Database for mCRC patients in France, Germany, Italy and Spain. All patients aged ≥21 years at mCRC diagnosis and with data collected during 2009 were included. Treatment patterns were examined descriptively by lines of therapy.. The study sample included 2682 mCRC patients. In first-line, more patients received FOLFOX (infusional 5-fluorouracil/leucovorin and oxaliplatin)- than FOLFIRI (infusional 5-fluorouracil/leucovorin and irinotecan)-, containing regimens in Germany (42 vs. 30%) and Spain (25 vs. 16%), while in Italy and France the reverse was true (Italy: 34% FOLFIRI vs.29% FOLFOX; France: 26 vs. 19%). In second-line, FOLFIRI-containing regimens were more commonly used than FOLFOX-containing regimens in Germany (36 vs. 18%), Italy (29 vs. 14%), and Spain (34 vs. 6%), while similar proportions of FOLFOX and FOLFIRI were used in France (18 vs. 15%). As part of first-line treatment, bevacizumab use ranged from 44% of patients in Italy to 30% in Spain, with slightly lower rates in second-line. Cetuximab first-line use ranged from 14% of patients in Spain to 7% in Italy, increasing in second-line to 30% in Spain, 26% in Italy, 20% in Germany, and 17% in France.. This analysis focused on description of treatment patterns, however, the actual clinical benefits of these treatment regimens on survival or quality of life were not addressed due to lack of relevant information in the data source. Some country differences in treatment patterns were observed. These differences might be partly explained by differences in local treatment guidelines, physician prescribing behaviours, reimbursement policies, and response to various regimens due to genetic differences.. In clinical practice in four European countries, FOLFOX- and FOLFIRI-based regimens are common standard of care chemotherapies for mCRC (FOLFOX and bevacizumab + FOLFIRI are the most common regimens), and monoclonal antibodies are often combined with these chemotherapies.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Europe; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome; Young Adult

The efficacy of bevacizumab combined with infusional 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan (FOLFIRI) as the second-line treatment for metastatic colorectal cancer (mCRC) has not been fully clarified, although bevacizumab combined with infusional 5-FU/LV plus oxaliplatin (FOLFOX) in the second-line setting has demonstrated a survival benefit. We investigated the efficacy of bevacizumab plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens without bevacizumab. Patients who received bevacizumab plus FOLFIRI or bevacizumab plus FOLFOX as second-line chemotherapy between July 2007 and March 2008 were registered (trial registration: UMIN000001547). Patient background data and progression-free survival (PFS), overall survival (OS), response, and bevacizumab-related adverse events were prospectively collected every 6 months. A total of 195 patients were enrolled from 26 institutions. Among them, 115 patients received bevacizumab plus FOLFIRI after failure of oxaliplatin and fluoropyrimidine (FOLFIRI+BV after OX/FU group), and 45 patients received bevacizumab plus FOLFOX after failure of irinotecan and fluoropyrimidine (FOLFOX+BV after IRI/FU group). Median PFS was 8.3 months (95% confidence interval [CI], 6.7-9.9) for the FOLFIRI+BV after OX/FU group and 7.8 months (95% CI, 5.8-9.7) for the FOLFOX+BV after IRI/FU group. Median OS was 21.6 months (95% CI, 17.6-25.6) and 16.5 months (95% CI, 11.8-21.2), respectively. Overall response rates were 25 and 29%, respectively. The most common grade≥3 bevacizumab-related adverse events were hypertension (5.0%) and bleeding (3.8%). FOLFIRI+BV after OX/FU showed comparable efficacy to FOLFOX+BV after IRI/FU.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

5-Fluorouracil (5-FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration-time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5-FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5-FU AUC-dose relationship are presented.. A set of 589 sequential patients from a clinical database receiving 5-FU, leucovorin, and oxaliplatin (the FOLFOX6 regimen) for colorectal cancer (CRC) treatment was analyzed. A subset including only patients who had at least two consecutive cycles tested, received 1,600-3,600 mg/m2 of continuous infusion 5-FU during the initial test cycle, and had a blood sample collected after ≥18 hours, was used to conduct regression modeling of the change in AUC versus change in dose.. A simple regression model with R(2) = 0.51 developed over n = 307 cycle-pair observations characterizes the AUC-Dose relationship as: change in AUC = 0.02063 * dose change. The model suggests that dose changes in the range of 145-727 mg/m2 would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg · h/L for most patients.. 5-FU is an ideal candidate for PK dose optimization. Because individual factors other than dose change may also affect the change in AUC, longitudinal PK monitoring in all cycles and dose adjustment to ensure AUC in the desired range of 20-30 mg · h/L are recommended.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Regression Analysis; Retrospective Studies

To determine the efficacy of bevacizumab in patients with metastatic colorectal cancer (MCRC) who have failed prior chemotherapy without bevacizumab.. Between March 2002 and June 2010, 40 patients in South Korea with MCRC who were treated with bevacizumab plus chemotherapy as a second or later-line treatment were analyzed retrospectively for their overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). The tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors guidelines.. All of the patients had progressed under prior chemotherapy without bevacizumab. Three patients (7.5%) exhibited an ORR, twenty one patients (52.5%) exhibited stable disease (SD), and fifteen patients (37.5%) exhibited disease progression. The median duration of the OS and PFS were 14.0 mo and 6.13 mo respectively. The median OSs were 16.60, 14.07 and 13.00 mo for second-line, third-line and fourth- or later-line treatments, respectively. The median PFSs were 7.23, 7.30 and 3.87 mo for the second-line, third-line and fourth- or later-line treatments, respectively.. In patients with MCRC, bevacizumab combined chemotherapy may be beneficial during second- or later-line treatment.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Republic of Korea; Retrospective Studies; Treatment Outcome

The vast majority of patients with pancreatic cancer present with locally advanced unresectable or metastatic disease, and in this setting only a palliative treatment can be offered. Single-agent gemcitabine has been considered the standard chemotherapy for patients with advanced pancreatic cancer since the results of a pivotal phase III trial showing superior clinical benefit compared to bolus 5-fluorouracil were published in 1997. In recent years, many randomized trials have attempted to improve results obtained with gemcitabine exploring a different schedule (fixed dose rate) of its administration, or testing the addition of one or more drugs to gemcitabine. Unfortunately, none of these trials produced a statistically significant and clinically relevant improvement in overall survival compared to the standard. A randomized phase III trial has recently shown a survival advantage using a combination of more drugs (FOLFIRINOX: irinotecan, oxaliplatin, folinic acid and 5-fluorouracil) compared to single-agent gemcitabine, suggesting that regimens without gemcitabine can be successfully used in patients with advanced pancreatic cancer. FOLFIRINOX was associated with worse toxicity than gemcitabine, and the available data suggest that this regimen may be considered for patients with metastatic pancreatic cancer who are fit enough to withstand potential side effects. The best option for these patients remains the enrolment in prospective clinical trials. Improvements in the treatment of the advanced disease will possibly derive from new combinations or from new drugs, but certainly from a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis and in invasion and metastasis.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase III as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

We aimed to clarify the prognostic significance of HER2 positivity in advanced gastric cancer.. The cohort included patients with initially metastatic or recurrent gastric cancer treated with first-line modified FOLFOX-6. The HER2 status was analyzed according to modified scoring criteria specific for gastric cancer.. HER2 positivity was shown in 10 out of 114 patients (9.0%). The median time-to-progression (TTP) (4.3 months, 95% confidence interval (CI)=3.6-4.9) and the overall survival (OS) (7.5 months, 95% CI=6.1-8.8) of patients with HER2-positive gastric cancer tended to be shorter than the median TTP (5.9 months, 95% CI=4.5-7.2) and OS (10.8 months, 95% CI=9.2-12.3) of those with HER2-negative gastric cancer (TTP, p=0.177; OS, p=0.068). Particularly in the subgroup of patients without diffuse-type histology, HER2-positive gastric cancer had a worse TTP than those with HER2-negative gastric cancer (p=0.024). In multivariate analysis of this subgroup, HER2 positivity and ECOG performance status of 2 were associated with shorter TTP (hazard ratio (HR)=2.926, p=0.014; HR=2.489, p=0.035, respectively).. HER2-positive gastric cancer seems to confer poorer prognosis, particularly in patients without diffuse-type tumor, treated with modified FOLFOX-6.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Fluorouracil; Genes, erbB-2; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Recurrence; Stomach Neoplasms; Treatment Outcome

A combination of 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX) is a standard regimen for the chemotherapy of metastatic colorectal cancer. The major dose-limiting toxic effect of oxaliplatin is neurotoxicity. The aim of this study was to evaluate the preventive effects of traditional Japanese medicines, goshajinkigan and shakuyakukanzoto on oxaliplatin-induced neurotoxicity with FOLFOX.. Between July 2006 and November 2008, a total of 44 patients with metastatic colorectal cancer received modified FOLFOX6 or FOLFOX4, as first-line chemotherapy at three institutions. They concurrently received either goshajinkigan (group A, n=20) or shakuyakukanzoto (group B, n=24) for neurotoxicity reduction.. The median number of treatment cycles and the median cumulative dose of oxaliplatin were 12 cycles (range, 4-19) and 898 mg/m(2) (range, 340-1255) in group A and 10.5 cycles (range, 6-20) and 845 mg/m(2) (range, 510-1480) in group B. Eighteen patients in group A and 24 in group B received oxaliplatin in a cumulative dose exceeding 500 mg/m(2). At a dose of 500 mg/m(2) oxaliplatin, grade 1-2 toxicity occurred in 10 patients of group A and in 7 of group B, but there was no grade 3 or higher toxicity in either group. The response rate of the 38 patients with measurable lesions was 50.0% (9/18) in group A and 65% (13/20) in group B.. The administration of traditional Japanese medicine may reduce oxalipatin-induced neurotoxicity without negatively affecting tumor response in patients with colorectal cancer who undergo FOLFOX therapy.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Drugs, Chinese Herbal; Female; Fluorouracil; Glycyrrhiza; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin; Paeonia; Retrospective Studies

To investigate the impact of concurrent chemoradiotherapy (CCRT) on stage IV rectum cancer.. Between 2000 and 2011, 297 consecutive patients diagnosed with stage IV rectum cancer (synchronous metastasis) were enrolled. Cox proportional hazard analyses were used for prognostic factors determination, and the Kaplan-Meier method was used for survival analyses. Propensity scores with the one-to-one nearest-neighbor matching model were used to select matched patients for validation studies.. In total, 63 patients received CCRT and 234 did not. The patients in the CCRT group were younger, had more low-lying lesions, and had more T4 lesions, lung metastases, metastasectomies, and oxaliplatin-based upfront chemotherapy. Before propensity-score matching, a younger age (HR = 0.662, P = 0.016), lower carcinoembryonic antigen (CEA) level (≤20 ng/ml) (HR = 0.531, P = 0.001), no metastasectomy (HR = 3.214, P < 0.001), and no CCRT (HR = 1.844, P = 0.019) were independent prognostic factors after controlling for other confounding factors. After matching, only CEA and metastasectomy, but not CCRT, were independent prognostic factors. The survival benefit of CCRT was restricted to patients who undergo subsequent metastasectomy.. Upfront CCRT only provided a survival benefit in patients with stage IV rectum cancer who undergo subsequent metastasectomy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoradiotherapy, Adjuvant; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Propensity Score; Rectal Neoplasms; Rectum; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds

Although current guidelines recommend distal resection margins (DRM) of 2-5 cm in rectal cancer operation, smaller margins may be safe. We therefore assessed the impact of distal margins on outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT) followed by radical resection or resection followed by adjuvant CRT.. This study involved 376 patients who underwent sphincter-saving resection for rectal adenocarcinoma and pre- or postoperative CRT between 2000 and 2006. DRMs were measured on pinned fixed specimens. We excluded patients who did not complete planned CRT and those with stage IV disease. A retrospective cross-sectional analysis was performed.. No significant differences in local recurrence (9.8 versus 7.3%; P = 0.324) and systemic recurrence (16.4 versus 18.7%; P = 0.731) were observed in patients with DRMs of ≤5 and >5 mm, respectively. Moreover, in each DRM category, there were no differences in local and systemic recurrence rates between patients who received pre- or postoperative CRT. DRM did not affect overall survival (P = 0.880) or 5-year survival rate (80.3 versus76.8%; P = 0.340).. A distal margin of at least 5 mm with negative resection margin on frozen section does not reduce oncological safety in rectal cancer patients who receive pre- or postoperative CRT.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy, Adjuvant; Cross-Sectional Studies; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Rectal Neoplasms; Rectum; Retrospective Studies; Survival Analysis; Treatment Outcome

Metastatic pancreatic carcinoma is an incurable disease and gemcitabine remains the standard of care in first-line chemotherapy. Recently, fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) demonstrated their superiority in first-line therapy. The objective of this study was to determine the efficacy of FOLFIRINOX in either first- and second-line treatment and to compare its efficacy in regard to the location of the primary tumor.. We performed a retrospective analysis of clinical factors associated with patients' survival using a cohort of 42 patients treated by FOLFIRINOX in either first- or second-line (2006-2011) and a control cohort of 42 patients matched on sex and age without FOLFIRINOX treatment was obtained from a previous period of time (2001-2005).. The median follow-up was 10 months. The median overall survival was 10 months for the whole cohort and 10 and 12 months for patients treated at first- and second-line, respectively (p<0.05). In this cohort using a multivariate model, among classical prognosis factors, only primary location in the head was associated with poor outcome. The median overall survival was 8 months for patients with primary location in the head and 14 months for patients with primary location in the corpse or tail (p=0.02). In the gemcitabine cohort, the median follow-up was 8 months. Using a multivariate model, only performance status was associated with outcome. The median overall survival was 9 versus 6.5 months for patients with tumor, of the head versus tail or corpse tumor respectively (p<0.05).. This retrospective study suggests the same efficacy of FOLFIRINOX used either in first- or second- line therapy for pancreatic cancer. Importantly, FOLFIRINOX compared favorably to gemcitabine only for patients with tumor of the corpse or tail. Further prospective trials are warranted to evaluate the efficacy of FOLFIRINOX in patients with tumor of the head of the pancreas.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Case-Control Studies; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Survival Rate; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Cetuximab; Colorectal Neoplasms; Device Approval; Drug Approval; Fluorouracil; Genetic Testing; Humans; Leucovorin; Mutation; Neoplasm Metastasis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; United States; United States Food and Drug Administration

The Avastin Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community-based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration.. The ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan-Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors.. In total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX-bevacizumab (n = 968) or FOLFIRI-bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX-bevacizumab and FOLFIRI-bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI-bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88-1.21) and OS (HR, 0.95; 95% CI, 0.78-1.16) outcome as with FOLFOX-bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies.. In first-line mCRC patients, the FOLFOX-bevacizumab and FOLFIRI-bevacizumab regimens were associated with similar treatment patterns and clinical outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Longitudinal Studies; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Treatment Outcome; Young Adult

Metastatic colorectal cancer is the second leading cause of cancer death in the United States. Since 1995, treatment regimens have included capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, aflibercept, and reforafenib. These medications have doubled the median survival of patients and improved the 5-year survival from less than 1% to 20%. Approximately 75% of patients stop first-line chemotherapy in clinical trials for reasons other than progressive disease and face the question of whether to consider "maintenance" chemotherapy or take a chemotherapy break. In this challenging case, Drs. Díaz-Rubio, Pietrantonio, and de Braud reflect on the data and offer their opinions. If each of the nearly 40,000 patients in the U.S. who face this decision chooses bevacizumab, the total cost is approximately $240 million per dose ($6,000 per infusion). The importance of this question and the cost to society are enormous.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Cost-Benefit Analysis; Deoxycytidine; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Maintenance Chemotherapy; Neoplasm Metastasis; Organoplatinum Compounds; Oxaloacetates

This retrospective study evaluated the outcome of adjuvant chemotherapy comprising modified FOLFOX6 (mFOLFOX6) after potentially curative metastasectomy from colorectal cancer.. The subjects were 40 patients with colorectal cancer who underwent potentially curative metastatectomy without any prior chemotherapy between December 2003 and November 2011. Patient background, type of adjuvant chemotherapy, and prognosis were examined.. Adjuvant chemotherapy was given in 30 patients (mFOLFOX6, n=26; oral fluoropyrimidines, n=4). The median relapse-free survival tended to be longer in patients treated with mFOLFOX6 compared to those treated with fluoropyrimidines (28.5 months vs 14.8 months; p=0.11). The median overall survival did not differ significantly between the 2 groups (37.9 months vs 31.3 months, p=0.56). When the analysis was restricted to patients treated with mFOLFOX6, no significant differences were found in relapse-free survival (p=0.46), overall survival (p=0.29), and frequency of adverse events during chemotherapy(Grade 3, p=0.32) between patients with synchronous metastasis(n=11) and those with metachronous metastasis (n=15).. These results suggest that mFOLFOX6 might contribute to prolonging the time to relapse and that the timing of developing metastasis(synchronously or metachronously) may not have any effect on the outcome of adjuvant mFOLFOX6.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Retrospective Studies

The -460T → C polymorphism of vascular endothelial growth factor (VEGF) gene significantly increases its promoter activity. A pilot study was conducted to assess the influence of this polymorphism on clinicopathological features of patients with colorectal carcinoma. In total, 228 patients were enrolled, including 100 with stage II/III colorectal carcinoma receiving curative surgery and 128 with metastatic disease. An excellent correlation in VEGF -460 genotypes based on white blood cells and tumor tissues existed, but there was no between-group difference in patients with or without colorectal carcinoma. A marked increase in intratumor and circulating VEGF levels were observed in patients with the T/C or C/C genotypes (P < 0.01), which was associated with increased extent of invasion, nodal involvement, poor histological differentiation, subsequent metastasis and shorter survival in stage II/III patients treated with curative surgery (P < 0.01). For patients with metastatic disease, this polymorphism was associated with a lower response rate to FOLFOX-4 (P = 0.03) and shorter survival (P < 0.001). By multivariate analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). These data suggest that -460T → C polymorphism of VEGF gene, by increasing VEGF expression and subsequent angiogenesis, could be a key determinant for increased tumor recurrence and a poor prognosis of patients with colorectal carcinoma. However, this study is exploratory and is not adjusted for multiple comparisons, requiring independent replication.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Polymorphism, Genetic; Treatment Outcome; Vascular Endothelial Growth Factor A

Several long-standing chemotherapy regimens are available to treat metastatic colorectal cancer (mCRC) including: oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (FOLFOX); and irinotecan plus 5-FU and leucovorin (FOLFIRI). More recently, new biologic therapies were approved for use in mCRC.. This study examined treatment patterns and trends in metastasectomy among newly diagnosed mCRC patients after the introduction of capecitabine (CAP) in 2001 and the biologic therapies in 2004.. Using a large, US-based administrative medical claims database of a national commercially insured population, patients with newly diagnosed mCRC were identified from 2001 to 2005. At least 6 months of patient history prior to mCRC diagnosis were required to confirm patients were newly diagnosed. Patients were followed from initial mCRC diagnosis to death, disenrollment, or 12/31/2006. Chemotherapy and biologic treatments and rates of metastasectomy over time were analyzed.. A total of 3781 mCRC patients met the study criteria. The average time from mCRC diagnosis to initiation of systemic treatment decreased from 134.4 days (SD 261.2) to 61.7 days (SD 89.3) in 2001-2005 (p < 0.001). The most common first-line regimens were FOLFIRI (40%), 5-FU/LV (31%), and capecitabine (21%) in 2001, and FOLFOX plus bevacizumab (22%), FOLFOX alone (15%), 5-FU/LV (15%), and capecitabine (15%) in 2005. Among patients with ≥1 year of follow-up, the use of biologics increased from 37.3% in 2004 to 52.0% in 2005 (p < 0.001). The percentage of patients who underwent resection after systemic treatment increased from 2.9% to 5.6% in 2001-2005 (p = 0.169).. Over time the standard of care chemotherapy for 1st-line mCRC has changed from FOLFIRI to FOLFOX, and the use of biologics has become common. The percentage of patients who underwent resection after systemic treatment almost doubled during the study period.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Camptothecin; Carcinoma; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Professional Practice; Standard of Care; Treatment Outcome; Young Adult

In patients with pancreatic cancer treated with curative resection, we evaluated the effect of clinicopathologic parameters on early distant metastasis within 6 months (DM6m) to identify patients who might benefit from surgery.. The study involved 84 patients with pancreatic cancer who had undergone curative resection between August 2001 and April 2009. The parameters of gender, age, tumor size, histologic differentiation, T classification, N classification, pre- and postoperative carbohydrate antigen (CA) 19-9 level, resection margin, and adjuvant chemoradiotherapy were analyzed to identify the risk factors associated with DM6m.. Of the 84 patients, locoregional recurrence developed in 35 (41.7%) and distant metastasis in 58 (69%). Of the 58 patients with distant metastasis, DM6m had developed in 27 (46.6%). Multivariate analysis showed that preoperative CA 19-9 level was significantly associated with DM6m (p<.05). Of all 84 patients, DM6m was observed in 9.1%, 50%, and 80% of those with a preoperative CA 19-9 level of ≤100 U/mL, 101-400 U/mL, and >400 U/mL, respectively (p<.001).. The preoperative CA 19-9 level might be a useful predictor of DM6m and to identify those who would benefit from surgical resection.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Capecitabine; Chemoradiotherapy; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Radiotherapy Dosage; Retrospective Studies

Standardized enumeration of CEC counts is required to minimize variability and allow cross-studies comparisons. The purpose of this paper is to identify CEC threshold proposal, by CellSearch system, for determining response to bevacizumab-based chemotherapy in metastatic colorectal cancer.. From July 2007 to June 2008, 33 patients treated with FOLFOX4 plus bevacizumab were enrolled in a prospective study. From January 2007 to June 2007, before bevacizumab was approved by the government in Japan, 31 patients treated with FOLFOX4 as a control were enrolled. CECs of whole blood at the baseline, day 4, 2 weeks after initiation of chemotherapy were isolated and counted using CellSearch system.. There was no correlation between CEC levels and the outcome in the FOLFOX4. In the bevacizumab-based chemotherapy, CEC levels at the baseline were significantly associated with the outcome. Patients with 65 or more CECs at the baseline had a shorter median PFS and OS, than the median PFS and OS of less than 65 CECs at the baseline in the bevacizumab-based chemotherapy (P = 0.003, P = 0.027, respectively). By univariate and multivariate Cox proportional-hazards regression, CEC levels (cut-off; 65) at the baseline indicated the strongest predictor for the outcome to bevacizumab-based chemotherapy.. A threshold of lower than 65 CECs, by the CellSearch System, at the baseline was a significant predictor of the outcome for colorectal cancer patients treated with bevacizumab-based chemotherapy.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cell Count; Cell Separation; Colorectal Neoplasms; Disease-Free Survival; Endothelial Cells; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Predictive Value of Tests; Prospective Studies; Regression Analysis; Survival Analysis; Young Adult

FOLFOX4 has been proven to be effective for metastatic colorectal cancer and is now used as a postoperative adjuvant therapy. However, adverse effects such as cold-sensitive paresthesia and bone marrow suppression are common, and this may necessitate a change of chemotherapy regimen even though FOLFOX is effective. PSK, a polysaccharide derived from mushrooms, has been developed in Japan as an immune-enhancing agent, and is widely used in patients with gastric, colorectal and pulmonary cancer. PSK has also been reported to decrease some adverse effects of chemotherapy. FOLFOX4 combined with PSK was administered to patients with metastatic colorectal cancer and the results were evaluated. Eight cycles of FOLFOX4 and PSK (3.0 g/day, po) were given to 25 patients with metastatic (19 hepatic, 3 pulmonary and 3 peritoneal) colorectal cancer. There was no CR (0%), while PR, SD and PD were 48, 36 and 16%, respectively. The response rate was 48%, and the disease control rate was 84%. There were significantly lower frequencies of adverse effects in comparison with published data. Grades 1 and 3 neutropenia occurred in 48 and 24%, respectively, of the patients; grades 1 and 3 nausea in 48 and 4%; and grades 1, 2 and 3 sensory neurotoxicity in 52, 4 and 0%. No patient dropped out due to adverse effect in this study. PSK plus FOLFOX4 seemed to be as effective as FOLFOX4 monotherapy as has been published, and significantly less toxic. These results suggest that this combination therapy may be more effective than FOLFOX4 monotherapy when given over a longer period, with a lower incidence of adverse effects.

Topics: Agaricales; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Peripheral Nervous System Diseases; Polysaccharides; Recurrence

Prognosis of metastatic gastric cancer is poor and median survival is between 3 and 5 months. Response rates of combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin in first-line treatment have been found to be 20-25% in the English literature. It has been demonstrated that adding docetaxel to combination chemotherapy improved time to progression and overall survival. However, the toxicity rates of the docetaxel-cisplatin-5-FU protocol were high. In our study we compared efficacy and toxicity of cisplatin-5-FU-folinic acid (CFF) and modified docetaxel-cisplatin-5-FU (mDCF) regimens in the first-line treatment of metastatic gastric cancer.. Between June 2004 and October 2008, 70 patients with previously untreated metastatic gastric cancer treated with CFF (n = 30) and mDCF (n = 40) were retrospectively evaluated in the study. Survival and toxicity data were compared.. Median age of the patients was 53 years (range 23-69). Forty-eight percent of the patients were male and 75.7% had an ECOG performance status of 0-1. Prognostic factors including age, ECOG performance status, histopathological grade, and number and sites of metastases were similar between the groups. Objective response rates (complete and partial response) were higher in the mDCF group (30.0 vs. 13.3%, p = 0.19). While toxicity was acceptable in both groups, the most common grade 3-4 toxicities were anemia in 3.3 and 5.0%, neutropenia in 20 and 7.5%, febrile neutropenia in 6.7 and 5.0%, and diarrhea in 3.3 and 5.0% in the CFF and mDCF groups, respectively. Median follow-up was 10.3 (1.5-59.6) months. During that period 90 and 97.5% of the patients were dead in the CFF and mDCF groups, respectively. Median time to progression was 4.4 (95% CI 1.8-7.0) and 6.2 months (95% CI 5.6-6.8) (p = 0.85), median overall survival was 6.5 (95% CI 1.8-11.2) and 8.7 months (95% CI 6.7-10.7) (p = 0.88) in the CFF and mDCF groups, respectively.. The mDCF regimen has been found to be more favorable than the CFF regimen with an acceptable toxicity profile in the first-line treatment of metastatic gastric cancer.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Docetaxel; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Retrospective Studies; Stomach Neoplasms; Survival Rate; Taxoids

The prophylactic effect of FOLFOX regimen, a standard regimen for unresectable colorectal cancer (CRC), was investigated in the adjuvant setting of CRC cases with distant metastases.. The study population included 116 CRC patients with synchronous metastases and 91 patients with metachronous metastases who had undergone curative operation in our hospital between 2000 and 2009. Clinicopathological parameters of CRC, postoperative chemotherapeutic regimen, recurrence rate, and relapse-free survival (RFS) were analyzed retrospectively.. After resection of CRC and synchronous metastases, 53 (84%) out of 63 patients without chemotherapy, and 38 (83%) out of 46 that received 5-fluorouracil (5-FU) alone or with leucovorin (LV) developed recurrent tumors. By contrast, only 1 (17%) among 6 patients who underwent FOLFOX treatment showed recurrence. The FOLFOX group exhibited significantly improved RFS as compared to the 5-FU (+ LV) or surgery-alone group (p = 0.03, p = 0.007, respectively). On the other hand, in patients with metachronous metastases, tumor-relapse rate and RFS were not significantly influenced by post-metastasectomy therapies.. In this retrospective analysis, the adjuvant administration of FOLFOX appeared to reduce the risk of relapse in a small group of CRC patients with synchronous metastases. Prospective randomized trials will be required to confirm the benefits of this management strategy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Logistic Models; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Retrospective Studies; Survival Rate

Regimens containing bevacizumab and 5-fluorouracil have achieved substantial progress in the treatment of colorectal cancer. However, individual responses to bevacizumab vary widely in regard to efficacy and toxicity.. To be able to select patients who would benefit from bevacizumab, we aimed to establish a predictor model for response to bevacizumab therapy based on gene expression profiles.. Retrospective analysis of tumor samples in the laboratory.. The patient population comprised 25 patients with metastatic colorectal cancer treated with bevacizumab with either modified FOLFOX6 or FOLFIRI, from whom tumor samples were available for gene expression analysis.. Response Evaluation Criteria in Solid Tumors were used to classify patients as responders or nonresponders to chemotherapy. Gene-expression profiles were determined with both microarray analysis and quantitative, real-time reverse-transcriptase polymerase chain reaction, and responders were compared with nonresponders, correcting for multiple comparisons. Genes that discriminated between groups on both analyses with the greatest accuracy were selected for the predictive model. Between-group differences in protein expression were confirmed with polymerase chain reaction and immunohistochemical staining.. From 19 probes that differentiated between responders and nonresponders on microarray analyses, we identified 13 genes that were differentially expressed between responders and nonresponders on both microarray and real-time reverse-transcriptase polymerase chain reaction. A model using the genes for vascular endothelial growth factor-A, thymidylate synthase, and tissue inhibitor of metalloproteinase 3 predicted response to bevacizumab therapy with an accuracy of 96%, sensitivity of 90.9% (10/11), specificity of 100% (14/14), positive predictive value of 100% (10/10), and negative predictive value of 93.3% (14/15). The protein expression of vascular endothelial growth factor-A, thymidylate synthase, and tissue inhibitor of metalloproteinase 3 correlated with the findings of mRNA expression analyses.. Validation of the model in a different cohort of patients is necessary.. The present predictive model based on quantitative, real-time, reverse-transcriptase polymerase chain reaction assessment of vascular endothelial growth factor-A, thymidylate synthase, and tissue inhibitor of metalloproteinase 3 may enable selection of colorectal cancer patients who would benefit from bevacizumab therapy.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression; Humans; Leucovorin; Male; Microarray Analysis; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Predictive Value of Tests; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sensitivity and Specificity; Thymidylate Synthase; Tissue Inhibitor of Metalloproteinase-3; Treatment Outcome; Vascular Endothelial Growth Factor A

Bevacizumab plus chemotherapy is a standard option in the treatment of metastatic colorectal cancer (mCRC). The aim of this study was to investigate the potential of circulating endothelial cell progenitors (CEPs) and phenotypical circulating endothelial cells (CECs) as surrogate markers of clinical outcome in mCRC patients to identify responders to bevacizumab in combination with chemotherapy.. A total of 69 patients with measurable mCRC were enrolled in this prospective study. Whole blood samples were analyzed before initiation of treatment and on days 4 and 14. Phenotypical CECs and CEPs were then isolated and enumerated by using flow cytometry.. CEP levels of less than 0.04% on day 4 were significantly associated with longer progression-free survival (PFS) and overall survival (OS) (P < .001, P = .002, respectively) as compared with levels of 0.04% or more. In addition, CXCR4-positive CEC levels of less than 20% at baseline were significantly associated with longer PFS and OS as compared other indicators investigated (P < .001, P = .002, respectively).. Levels of CEPs on day 4 and proportion of CXCR4-positive CECs at baseline were correlated with the prognosis of bevacizumab combination chemotherapy, suggesting that these surrogate markers may play a core role in the selection of candidates for bevacizumab treatment.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Colorectal Neoplasms; Disease-Free Survival; Endothelial Cells; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Receptors, CXCR4; Stem Cells; Treatment Outcome

We investigated the effectiveness of prophylactic FOLFOX after curative resection of synchronous metastases in patients with colorectal cancer (CRC). Clinicopathological information including postoperative chemotherapy, such as a therapeutic regimen, relapse-free survival (RFS), site of recurrence, etc., was retrospectively analyzed in 116 CRC patients with synchronous distant metastases, and 63 patients with metachronous metastases who had received surgery in our hospital between 2000 and 2009. Fifty-three patients (84%) out of 63 without adjuvant chemotherapy, and 38 (83%) out of 46 patients that received oral or intravenous 5-fluorouracil (5-FU) (alone or with leucovorin (LV)or isovorin) developed recurrent tumor(s) afterwards. The median RFSs were 119 and 281 days, respectively. By contrast, a single patient among 6 who underwent FOLFOX (up to 12 therapeutic courses) showed recurrence 476 days after surgery. The RFS of the FOLFOX was significantly higher than that of the 5-FU (+LV) or surgery alone (p=0. 03, p=0. 007, respectively). In conclusion, the FOLFOX regimen is more beneficial for CRC patients with synchronous metastasis as adjuvant chemotherapy than 5-FU (+LV) or other followup strategies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Recurrence; Retrospective Studies

The ability of molecular targeting agents to improve overall survival (OS) in metastatic colorectal cancer (MCRC) patients who underwent oxaliplatin-based chemotherapy remains controversial.. We retrospectively analyzed 331 patients with MCRC who underwent first-line oxaliplatin-based chemotherapy. Treatment outcomes were compared between patients who started chemotherapy from April 2005 to March 2007 (cohort A; n = 157) and those who started it from April 2007 to March 2009 (cohort B; n = 174). To evaluate the impact of exposure to agents, we applied time-varying covariate analysis to avoid possible lead-time bias.. Median OS of cohorts A and B was 21.3 and 28.6 months, respectively (HR 0.66, 95% CI 0.50-0.87, p = 0.003). Exposure to bevacizumab (25 vs. 76%), anti-epidermal growth factor receptor (EGFR) (18 vs. 33%) or curative surgery after chemotherapy (4 vs. 10%) was significantly higher in cohort B. According to a multivariate Cox model with exposure to each agent or treatment as a time-varying covariate, hazard ratios of death were 0.71 (95% CI, 0.51-0.96; p = 0.03) for bevacizumab, 0.62 (95% CI, 0.40-0.89; p = 0.01) for anti-EGFR and 0.22 (95% CI, 0.06-0.57; p = 0.004) for surgery.. Increased exposure to molecular targeting agents or surgery after chemotherapy appears to contribute to an improvement in OS in recent patients with MCRC who have undergone oxaliplatin-based chemotherapy.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cohort Studies; Colorectal Neoplasms; Combined Modality Therapy; ErbB Receptors; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Molecular Targeted Therapy; Multivariate Analysis; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Retrospective Studies; Survival Rate; Treatment Outcome

Although surgical resection alone has been validated as a standard treatment for patients with liver metastases from colorectal cancer, a high rate of recurrence is still an issue to be overcome. We aimed to assess the efficacy of adjuvant chemotherapy using an oxaliplatin-based regimen in patients who underwent hepatic and primary colorectal cancer resection.. Sixty patients who received oxaliplatin-based postoperative chemotherapy combined with curative resection of primary colorectal cancer and synchronous liver metastases between January 2000 and February 2008 were retrospectively reviewed. The Kaplan-Meier method was used to estimate survival, and prognostic factors were evaluated with the log-rank test.. Median overall survival (OS) was 62.8 months [95% confidence interval (CI) 44.1-81.3], and median relapse-free survival (RFS) was 32.8 months (95% CI 5.8-59.6). The 1-, 3- and 5-year survival rates were 95.0, 68.8 and 55.5%, respectively. The relapse-free interval and modality of liver resection were independently associated with OS.. Oxaliplatin-based adjuvant chemotherapy after radical resection resulted in increased OS and RFS with acceptable tolerability compared to surgery alone. However, it is not yet clear whether postoperative oxaliplatin-based chemotherapy improves outcome compared to patients treated with 5-fluorouracil plus leucovorin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate

The current study was conducted to retrospectively investigate the effects of reducing average relative dose intensity (ARDI) in response to adverse events on time to treatment failure (TTF) and overall survival (OS) in patients with metastatic or recurrent colorectal cancer receiving modified FOLFOX6 (mFOLFOX6) therapy between January 2006 and May 2010. Patients were divided into two groups based on ARDI: those with an ARDI of 85% or more (ARDI maintained; n = 12) and those with an ARDI of less than 85% (ARDI reduced; n = 37). In the ARDI-reduced group, out of a total of 402 treatment courses conducted, 25.9% involved treatment delays and 8.2% involved dose reductions, and the incidence rate of treatment delay was significantly higher than that of dose reduction (p < 0.001). Hematological toxicity was the main reason for both treatment delays and dose reductions. Reduced ARDI by dose reduction effectively prevented any increase in the severity of neutropenia and the treatment delays in the next courses, suggesting that the dose reductions were appropriately performed. Median TTF in the ARDI-maintained and ARDI-reduced groups was 5.2 and 5.8 months, respectively (p = 0.225). Median OS was 15.5 months and 33.9 months in the ARDI-maintained and ARDI-reduced groups, respectively (p = 0.347). These findings suggested that reductions in ARDI of mFOLFOX6 therapy for metastatic or recurrent colorectal cancer due to treatment delays and dose reductions in response to adverse events do not necessarily lead to shortened TTF and OS.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Retrospective Studies

Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), has been proven to be efficient in metastatic colorectal cancer (mCRC); however, the therapeutic response is variable and markers predictive of response are urgently required. This study was conducted to determinate the predictive values of KRAS mutation status and EGFR expression in mCRC patients treated with cetuximab plus chemotherapy.. Clinical benefit with EGFR-targeting antibodies seems to be restricted to a particular subgroup of mCRC patients. Therefore, the identification of reliable predictive factors for mCRC patients is imperative before the introduction of targeted chemotherapy.. Ninety-five mCRC patients receiving cetuximab plus the FOLFIRI or FOLFOX-4 chemotherapy were enrolled into the present study. KRAS mutation status/EGFR expression levels were analyzed using direct sequencing, immunohistochemistry (IHC), and reverse transcription-polymerase chain reaction (RT-PCR) assay, respectively. The association between clinical response, progression-free survival (PFS) and overall survival (OS) as well as KRAS mutation status/EGFR expression levels were evaluated.. Of 95 mCRC patients, KRAS mutations were identified in 41 cases, and EGFR overexpression (protein or mRNA levels) were observed in 78 patients. Among 41 tumors with KRAS mutation, 33 were found to be activating mutants at codons 12, 13, 15 or 18, while 8 were nonactivating mutants at codons 20, 30, or 31. Fifty-five patients responded to cetuximab plus chemotherapy, 49 were EGFR overexpression and 46 were wild-type KRAS tumor status. Patients with tumors that express high EGFR levels or harbor wild-type KRAS are more likely to have a better PFS and OS when treated with cetuximab plus chemotherapy (all P < 0.05). Furthermore, patients with nonactivating KRAS mutants in tumors had a significantly better PFS and OS than patients with activating KRAS mutants (both P < 0.05). However, for patients with wild-type KRAS tumor status, EGFR expression remains a relevant predictor of clinical response.. The study suggests that activating KRAS mutants is a particularly important independent predictive marker in mCRC patients treated with cetuximab plus chemotherapy, of which combing activating KRAS mutants and EGFR could help to identify the subgroup of patients who are most likely to respond to cetuximab plus chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Predictive Value of Tests; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Retrospective Studies

This report presents a rare patient with cardiac tamponade as the first manifestation of primary gastric signet-ring cell carcinoma.. A 56-year-old woman with emergent dyspnea, anterior chest oppression, and hypotension was diagnosed as having cardiac tamponade due to massive pericardial effusion. The endoscopic examination of the stomach disclosed gastric cancer in the posterior wall of the antrum and the biopsy showed signet-ring cell carcinoma. The gastric cancer was complicated by malignant pericardial effusion and pleural effusion as well as metastasis to the peripheral lymph nodes and bones. The patient was treated with percutaneous pericardiocentesis followed by systemic chemotherapy (oxaliplatin and sequential 5-fluorouracil plus leucovorin). The pericardial effusion gradually disappeared and there was no cardiac tamponade occurrence. The patient has survived more than 6 months so far.. Cardiac tamponade may originate from a primary gastric signet-ring cell carcinoma. Pericardiocentesis followed by systemic chemotherapy may be effective in controlling such advanced gastric signet-ring cell carcinoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Signet Ring Cell; Cardiac Tamponade; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Radiography; Stomach Neoplasms; Treatment Outcome

Bevacizumab has been demonstrated to prolong survival in patients with metastatic colorectal cancer when used in combination with chemotherapy. We investigated the efficacy of chemotherapy administered in our general hospital for patients with metastatic colorectal cancer after the introduction of FOLFOX/FOLFIRI (+/-bevacizumab) therapy.. The subjects in this study were 34 patients diagnosed with metastatic colorectal cancer, who received either FOLFIRI (+/- bevacizumab) or mFOLFOX6 (+/-bevacizumab) therapy in this hospital. The subjects were divided into a bevacizumab combination regimen group (those who received the regimen as first-line treatment), and a non-bevacizumab combination regimen group (those who did not receive the regimen as first-line treatment). Comparisons were made with regard to anticancer efficacy, progression-free survival time, and overall survival time.. Comparison between the bevacizumab combination regimen group and the non-bevacizumab combination regimen group, revealed no significant difference due to the small number of relevant patients. However, the former showed a slight advantage over the latter in terms of anti-cancer efficacy and progression-free survival time.. Bevacizumab is expected to contribute to the prolongation of survival in patients in our general hospital.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Hospitals, General; Hospitals, Public; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Survival Rate; Tomography, X-Ray Computed; Treatment Outcome

In colorectal cancers, the local cytokine network and the levels of nitric oxide (NO) and reactive oxygen species (ROS) are known to be closely related to cancer progression and metastasis, but the influence of the currently administered therapies on the cancer microenvironment is not completely understood. We analyzed the levels of reactive oxygen species (ROS), nitric oxide (NO), and cachexia-mediated cytokines (IL-1beta, IL-6, TNF-alpha) in cocultures of human colon carcinoma spheroids prepared with cells derived from tumors of different grades with human normal colon epithelial and myofibroblast cells and normal endothelial cells. We also analyzed the influence of standard chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) combined with camptothecin (CPT-11) (IFL regimen with drug concentrations adjusted to in vitro conditions) on these parameters. The results indicated that adhesion of colon carcinoma spheroids to colon epithelium and myofibroblast monolayers induced O2- anion production but decreased NO levels compared to the sum of the radicals released by monocultures of the two types of cells. Coculture of colon carcinoma spheroids with endothelium was an exception to this rule, as only HT29 cells decreased NO production. In cocultures, anticancer drugs additionally, though only slightly and insignificantly, increased the production of the radicals compared to a nontreated coculture, but in monocultures, the drugs, and especially CPT-11, were ROS inducers and simultaneously NO production inhibitors. However, the levels of released ROS and NO were dependent on the stage of colon carcinoma that the cells were derived from. LS180 cells (grade B) grown in monocultures produced the lowest ROS levels but were the best producers of NO. Adhesion of tumor spheroids to normal cells influenced the microenvironmental cytokine network compared to monocultures, decreasing IL-1beta and TNF-alpha secretion but significantly enhancing L-6 levels. The addition of the drugs had no effect on IL-1beta levels but increased TNF-alpha production and lowered the amounts of IL-6. In conclusion, cytotoxic drugs may, dependent on the stage of tumor growth or the type of chemotherapy regimen administered, significantly influence the proinflammatory cytokine network and local ROS and NO levels. Moreover, in cocultures of tumor cells with normal epithelial, myofibroblast, and endothelial cells, ROS production seems to be involved in local cell injury, which was detect

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Coculture Techniques; Colon; Colonic Neoplasms; Cytokines; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Nitric Oxide; Reactive Oxygen Species; Spheroids, Cellular

We retrospectively investigated the safety and efficacy on outpatient chemotherapy including bevacizumab(BV)as secondline therapy for inoperable metastatic colorectal cancer. Analytical subjects were thirty patients treated with chemotherapy including BV as second-line therapy after first disease progression. All patients were treated with BV 5mg/kg. Concurrent therapy was given mFOLFOX6(2 patients)and FOLFIRI(28 patients). The BV treatment frequency and all course treatment frequency including the prior regimens averaged 20 and 37 times, respectively. The overall response rate was 24. 1%(PR, 7 patients; SD, 17 patients; PD, 5 patients), and the median duration of progression-free survival was 8. 0 months. The median duration of survival after addition of BV was 20. 3 months. The adverse events were 84%(>grade 3, 9%), BV-associated adverse events were GI perforation(1 patient), GI hemorrhage(1 patient), grade 3 hypertension(1 patient)and grade 2 epitaxis(2 patient). Although it is necessary to be careful about GI hemorrhage and GI perforation, we could safely continue the treatment with BV on outpatient chemotherapy. We confirmed that the chemotherapy including BV as second-line therapy had high antitumor effect and patient benefit.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Salvage Therapy; Survival Rate

Recently, significant progress in treatment of metastatic colorectal cancer has been achieved. Either FOLFIRI (fluorouracil, leucovorin and irinotecan) or modified FOLFOX6 (fluorouracil, leucovorin and oxaliplatin, oxaliplatin dose 85 mg/m(2)) is selected as first-line therapy in clinical practice in Japan. However, economic burden of colorectal cancer is considerable.. Analysis was made for all patients who were treated with FOLFIRI or modified FOLFOX6 for metastatic colorectal cancer. Regimen of FOLFIRI was compared with modified FOLFOX6 under consideration from clinical and economic standpoints. Progression free survival, response, toxicity and cancer care cost in patients with metastatic colorectal cancer was analyzed. Direct costs based on the fee schedule of the Japanese national health insurance were calculated.. Median progression free survival was 7.7 months for FOLFIRI versus 8.4 months for modified FOLFOX6 (P = 0.48). Overall cost for first four cycles was yen756 284 for FOLFIRI and yen1 081 162 for modified FOLFOX6 (P < 0.0001). All grade alopecia was significantly more frequent with FOLFIRI than with modified FOLFOX6 (P = 0.04). All grade neuropathy was more observed with modified FOLFOX6 than FOLFIRI (P = 0.0002).. FOLFIRI is inexpensive in the initial stage of treatment which a number of patients can receive chemotherapy than modified FOLFOX6 as first-line therapy for metastatic colorectal cancer in Japanese national insurance system.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Costs and Cost Analysis; Disease-Free Survival; Dose-Response Relationship, Drug; Fee Schedules; Fluorouracil; Japan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies; Treatment Outcome

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Appendicitis; Colectomy; Colonoscopy; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Incidental Findings; Leucovorin; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Thoracic Surgery, Video-Assisted; Tomography, X-Ray Computed

Combination of bevacizumab and FOLFIRI has currently become one of the standard therapeutic regimens. However, published information is still limited. The objective of the present retrospective observational study is to analyse the response and toxicity of first-line treatment with FOLFIRI+bevacizumab in patients with metastatic colorectal cancer (mCRC).. Data were collected from patients from nine Spanish sites diagnosed with mCRC, ECOG≤2, whose first treatment for advanced disease was at least three cycles of FOLFIRI+bevacizumab.. A total of 95 patients were enrolled into the study: 64.2% males, median age of 59 years (53.2-67.1 years), ECOG=0-1 in 96.9% of patients. The main site of primary tumour was the colon (69.7%), and most metastases occurred in the liver (71.6%). Clinical benefit was detected in 67.4% (57.0-76.6; 95% confidence interval (CI)), with 8.4% of CR and 42.1% of PR. Median TTP was 10.6 months (10.0-11.3; 95% CI), PFS was 10.6 months (9.8-11.3; 95% CI), and OS was 20.7 months (17.1-24.2; 95% CI). Main grade I-II toxicities included haematological toxicity (35.8%), diarrhea (27.3%), mucositis (25.3%), asthenia (19.0%), haemorrhages (11.6%), and emesis (10.6%). Toxicities reaching grades III-IV were haematological toxicity (9.5%), diarrhea (8.5%), mucositis (5.3%), hepatic toxicity (2.1%), asthenia (2.1%), proteinuria (1.1%), emesis (1.1%), pain (1.1%), and colics (1.1%).. Results of this study support the beneficial effect of adding bevacizumab to FOLFIRI regimen in terms of efficacy and show a favourable tolerability profile.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Disease Progression; Drug Tolerance; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Rectal Neoplasms; Retrospective Studies; Safety; Spain; Treatment Outcome

More than half of patients with pancreatic adenocarcinoma (PA) are candidates for further treatment when they experience upfront treatment failure.. Patients with gemcitabine-resistant PA, age <76 years and Karnofski performance status (KPS) >50 were treated with a XELIRI or FOLFIRI regimen until progressive disease or a maximum of six months. As this was an observational study, no statistical design was performed.. Between July 2007 and December 2009, 34 patients (median age 60 years; median KPS 90) were treated with XELIRI (26) or FOLFIRI (8) regimen. Grade >2 toxicity consisted of neutropenia in 9% of patients, anemia and fatigue in 3% and hand-foot syndrome in 12%. Median progression-free survival was two months (range 1-4). Maximum response was stable disease in four patients (12%). Median survival was 4.2 (range 1-15) months.. Fluoropyrimidine and irinotecan combination does not seem to have any role in the treatment of gemcitabine-resistant PA.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Salvage Therapy; Survival Rate; Treatment Outcome; Young Adult

The absence of treatment standards for the use of chemotherapy in pregnancy is due, in part, to the fact that cancer in the gravid female is relatively uncommon.. A case (of a pregnant woman with newly diagnosed colorectal cancer) is presented to explore this area of medical uncertainty.. Managed by a multi-disciplinary team, successful prolongation of gestation was achieved with an oxaliplatin-based chemotherapy regimen.. A perspective of the ongoing conflict between prolonging the mother's life and preserving fetal development is highlighted. Although not life-saving, administration of chemotherapy in this woman was life-sparing.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Treatment Outcome

Small-bowel adenocarcinoma (SBA) is rare. No standard chemotherapy for this type of cancer has yet been established. At Cancer Institute Hospital (CIH), the chemotherapy regimen used for colorectal cancer is initially used for patients with SBA, followed by that used for gastric cancer.. Patients with advanced or recurrent SBA who had been treated with chemotherapy in CIH were retrospectively analyzed. The first-line treatments were fluoropyrimidines used alone or in combination with other drugs, such as 5-fluorouracil plus leucovorin (FL), UFT-E, or TS-1. The second-line treatment was irinotecan (CPT-11) monotherapy.. Fluoropyrimidine-based regimens, mainly FL, were used for 10 patients. Seven patients received the second-line CPT-11 regimen. Disease control was seen in five patients (50%) with the first-line chemotherapy and in three (43%) with the second-line. The median overall survival time was 12 months (range 3-39). The treatments were generally tolerated. Gastrointestinal symptoms were the most common adverse effects.. Fluoropyrimidines as the first-line and CPT-11 as the second-line chemotherapy yielded low response, although the adverse effects were mild. The FOLFOX and FOLFIRI regimens such as those used for metastatic colorectal cancer are potential alternative strategies. Extensive trials are needed to develop standard chemotherapy with new drugs.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease Progression; Female; Fluorouracil; Follow-Up Studies; Humans; Intestinal Neoplasms; Intestine, Small; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Survival Rate; Tomography, X-Ray Computed; Vitamin B Complex

We retrospectively analysed 153 patients with metastatic colorectal cancer who received FOLFOX with or without bevacizumab as first-line chemotherapy. Several background characteristics and chemotherapy features (grade of neutropaenia, use of bevacizumab or irinotecan, re-introduction of FOLFOX, and tumour progression) as time-varying covariates were analysed as potential prognostic factors. Of the 153 patients, mild neutropaenia (grade 1-2) occurred in 60 patients (39%) and severe neutropaenia (grade 3-4) occurred in 46 patients (30%). The other 47 patients (31%) did not experience neutropaenia. According to a multivariate Cox model with time-varying covariates, hazard ratios (HRs) of death were 0.55 (95% confidence interval (CI), 0.31-0.98; P=0.044) for patients with mild neutropaenia and 0.35 (95% CI, 0.18-0.66; P=0.002) for those with severe neutropaenia. Both mild and severe neutropaenia during chemotherapy are associated with improved survival in patients with MCRC. Prospective trials are required to assess whether dosing adjustments based on neutropaenia may improve chemotherapy efficacy.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Prognosis; Retrospective Studies; Severity of Illness Index; Treatment Outcome

A 68-year-old man underwent laparoscopic low anterior resection for rectal carcinoma in December 2006. Nearly 19 mo after the operation, he developed recurrent rectal cancer with peritoneal metastasis. In September 2008, he subsequently underwent a laparotomy with a peritonectomy, omentectomy, splenectomy, and a Hartmann procedure. Hyperthermic intraperitoneal oxaliplatin 750 mg was administered. The patient was discharged with no postoperative complications and has been well with postoperative FOLFOX chemotherapy.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fluorouracil; Humans; Laparoscopy; Leucovorin; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Rectal Neoplasms; Treatment Outcome

In the movement towards individualized treatment regimens, Rothenberg et al. validate XELOX as another available systemic therapy for patients being treated with second-line treatment for metastatic colorectal cancer. This paper adds to a growing body of data in the first-line and second-line setting that confirms the noninferiority of oral fluoropyrimidine-containing regimens.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Disease-Free Survival; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome

Oxaliplatin is the third-generation platinum complex to be active in advanced colorectal cancer. In Japan, it was approved in April 2005. FOLFOX regimen(a combination of leucovorin and fluorouracil with oxaliplatin) has been one of the standard chemotherapy regimens for metastatic colorectal cancer.. To evaluate the efficacy and feasibility of FOLFOX4 and mFOLFOX6 regimens as first-line chemotherapy in Japanese patients with metastatic colorectal cancer, 23 consecutive patients with histologically confirmed colorectal cancer who were treated between June 2005 and August 2007 were investigated in this retrospective study. FOLFOX4 was used for treatment in 13 patients(57%), and mFOLFOX6 was in 10 patients(43%).. The objective response rate was 50.0%. The median survival time was 17.4 months. The median number of cycles was 8.0, with a median relative dose intensity of 74.5% for oxaliplatin. Grade 3 or 4 hematological toxicities were leukocytopenia in four patients, and neutropenia in 12 patients, while non-hematological toxicities such as nausea, anorexia and sensory neuropathy occurred in only one patient each adverse event. No treatment-related deaths occurred.. FOLFOX regimen has good efficacy in Japanese patients with metastatic colorectal cancer as first-line chemotherapy, with an acceptable overall toxicity profile.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Survival Rate; Treatment Outcome

Previously we developed membrane-arrays as a promising tool to detect circulating tumor cells (CTC) with KRAS oncogene in patients with malignancies. This study was conducted to determinate the predictive values of CTCs with KARS mutation by membrane-arrays for metastatic colorectal cancer patients treated with cetuximab plus chemotherapy.. Seventy-six metastatic colorectal cancer patients receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy were enrolled. KRAS mutation status in the peripheral blood of these patients was analyzed using membrane-arrays, and KRAS mutation status in tumors was analyzed by DNA sequencing.. Among 76 metastatic colorectal cancer patients, KRAS mutations in tumors and in peripheral blood were identified in 33 (43.4%) and 30 (39.5%) patients, respectively. The detection sensitivity, specificity, and accuracy of membrane-arrays for CTCs with KRAS oncogene were 84.4%, 95.3%, and 90.8%, respectively, and indeed a highly significant correlation to KRAS mutations in tumors (P < 0.0001) was observed. Forty-five (59.2%) patients responded to cetuximab plus chemotherapy, and 41 and 40 were wild-type KRAS in tumors and peripheral blood, respectively (both P < 0.0001). Patients with tumors that harbor wild-type KRAS are more likely to have a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Likewise, patients with CTCs of wild-type KRAS in peripheral blood express a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001).. These findings provide evidence that detection of KRAS mutational status in CTCs, by gene expression array, has potential for clinical application in selecting metastatic colorectal cancer patients most likely to benefit from cetuximab therapy.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Cetuximab; Colorectal Neoplasms; DNA Mutational Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Retrospective Studies; Treatment Outcome

To investigate three genetic alterations (TP53 mutation, Kras mutation and microsatellite instability (MSI)) and three polymorphisms (methylene tetrahydrofolate reductase (MTHFR) C677T, excision repair cross complementing group 1 (ERCC1)-118 and X-ray repair cross complementing group 1 (XRCC1)-399) for their ability to predict response, survival and toxicity to FOLFOX first line chemotherapy in the treatment of metastatic colorectal cancer (mCRC).. Tumour tissues from 118 mCRC patients who underwent FOLFOX treatment from three successive phase II trials were evaluated for mutations in TP53 (exons 5-8) and Kras (codons 12 and 13) and for MSI using PCR-based analysis. Genotyping for common single nucleotide polymorphisms in the MTHFR (codon 677), ERCC1 (codon 118) and XRCC1 (codon 399) genes was also carried out using PCR techniques. These genetic markers were correlated with clinical response, survival and toxicity to treatment.. Patients with the T allele of ERCC1-118 showed significantly worse progression-free survival in univariate analysis (HR=2.62; 95% CI=1.14-6.02; P=0.02). None of the genetic alterations or polymorphisms showed significant association with clinical response to FOLFOX. The MTHFR, ERCC1 and XRCC1 polymorphisms showed no associations with overall haematological, gastrointestinal or neurological toxicity to FOLFOX, although MTHFR 677 TT genotype patients showed a significantly higher incidence of grade 3 or 4 diarrhoea (26%) compared with CC or CT genotype patients (6%, P=0.02).. The ERCC1-118 and MTHFR C677T polymorphisms were associated with progression and severe diarrhoea, respectively, after FOLFOX treatment in mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Genes, p53; Genotype; Humans; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; X-ray Repair Cross Complementing Protein 1

The anti-VEGF antibody bevacizumab associated with an irinotecan or oxaliplatin-based chemotherapy was proved to be superior to the chemotherapy alone in first or second line treatment of metastatic colorectal cancer (mCRC). However, it was reported to have no efficacy in 3rd or later-line, alone or with 5FU. The aim of this study was to evaluate the activity of bevacizumab combined with FOLFIRI or FOLFOX in mCRC who have failed prior chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin.. Thirty one consecutive patients treated between May 2005 and October 2006 were included in this retrospective study. All of them have progressed under a chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin and received bevacizumab (5 mg/kg) in combination with FOLFIRI or simplified FOLFOX4 every 14 days.. Ten patients (32.2%) had an objective response (1 CR, 9 PR) and 12 (38.8%) were stabilized. The response and disease control rates were 45.4% and 100% when bevacizumab was administered in 2nd or 3rd line and 25% and 55% in 4th or later line respectively (p = 0.024 and p = 0.008). Among the patients who had previously received the same chemotherapy than that associated with bevacizumab (n = 28) the overall response rate was 35.7% and 39.3% were stabilized. Median progression free survival (PFS) and overall survival (OS) were of 9.7 and 18.4 months respectively. Except a patient who presented a hypertension associated reversible posterior leukoencephalopathy syndrome, tolerance of bevacizumab was acceptable. A rectal bleeding occurred in one patient, an epistaxis in five. Grade 1/2 hypertension occurred in five patients.. This study suggests that bevacizumab combined with FOLFOX or FOLFIRI may have the possibility to be active in chemorefractory and selected mCRC patients who did not receive it previously.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies; Young Adult

We performed a single-institution retrospective study to evaluate the efficacy and toxicities of oxaliplatin, 5-fluorouracil (5-FU), leucovorin (LV) combination chemotherapy as salvage treatment in patients with metastatic or advanced gastric cancer.. Sixty-two patients with advanced gastric cancer previously treated were eligible for the study. Patients received oxaliplatin 100 mg/m(2) and LV 100 mg/m(2) (2-h intravenous infusion) followed by 5-FU 2,400 mg/m(2) (46-h continuous infusion) every 2 weeks, and responses were assessed after every three cycles.. Fifty-nine out of 62 patients were assessable for response. Among them, 46 patients had previously been treated with cisplatin based chemotherapy. Patients had a median age of 57 years (range 32-76 years), 72.6% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Total 296 courses of chemotherapy were administered as second-line (67.7%) or third-line (27.4%), and the median courses per patient was three cycles. Out of 59 evaluable patients, 14 partial responses were observed (overall response rate, 22.6%). Stable disease was observed in 22 patients (35.5%), and progressive disease in 23 patients (37.1%). The median response duration, time to progression, and overall survival were 2.3, 3.0, and 8.0 months, respectively. The major toxicities were neutropenia, mucositis, and peripheral neuropathy. Grade 3 or 4 hematologic toxicities included neutropenia in nine patients (14.5%) and thrombocytopenia in one patient (1.6%). Other grade 3 or 4 toxicities included mucositis in one patient (1.6%) and vomiting in two patients (3.2%). Grade 1 or 2 peripheral neuropathy were observed in 18 patients (29.0%), however there were no cases of grade 3 or 4 peripheral neuropathy and no treatment-related deaths.. The combination of oxaliplatin, 5-FU and LV was effective and safe salvage chemotherapy in advanced gastric cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Salvage Therapy; Stomach Neoplasms; Survival Analysis; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates

A 54-year-old woman visited our hospital with a chief complaint of lower abdominal pain and melena. The patient was diagnosed with sigmoid colon cancer using colonoscopy. Abdominal CT revealed metastases to para-aortic lymph node, so our diagnosis was unresectable sigmoid colon cancer. She underwent a transverse colostomy to avoid stenosis. Two weeks after surgery, she underwent a 1-week chemotherapy regimen (CPT-11 80 mg/m(2)/week+5-FU 2,000 mg/m(2)/week+l-LV 250 mg/m(2)/week) modified AIO regimen combined irinotecan for 3 weeks, followed by a 1-week rest interval as one course. Throughout the period of treatment, there was no adverse event, and this regimen has been maintained for 5 courses. After 5 courses of chemotherapy, primary tumor and metastases to para-aortic lymph nodes were remarkably reduced on colonoscopy and abdominal CT. So, she could undergo curative resection. Pathological efficacy was Grade 3, a complete response. This combination therapy may well be useful for advanced colon cancer patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aorta; Camptothecin; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Neoplasm Metastasis; Sigmoid Neoplasms; Tomography, X-Ray Computed

Oxaliplatin is a therapeutic platinum compound used for the treatment of colorectal cancer; however, it might induce hypersensitivity reactions, a critical situation that requires discontinuation of chemotherapies that contain oxaliplatin. Independent attempts of oxaliplatin desensitization have been reported, with mostly successful results. This letter reports a 53-year-old Japanese woman (weight, 70 kg) with chemorefractory metastatic rectal cancer who had undergone surgical intervention twice and received 3 treatment regimens. The patient developed grade 3 hypersensitivities to oxaliplatin during cumulative cycles of the FOLFOX (5-fluorouracil/leucovorin/oxaliplatin)-4 regimen. After the subsequent regimen failed, she was desensitized using a protocol of an 8-hour series of diluted-oxaliplatin infusions. Because, according to previously published desensitization reports, hypersensitivity reactions might recur during the final bag infusion of oxaliplatin despite intensive premedication, prophylactic antiemesis, corticosteroids, and antihistamines were administered twice (ie, before and during the oxaliplatin infusion). Allergic reactions were successfully and efficiently prevented with the 2 stages of intensive premedication in this patient who was able to receive oxaliplatin and had stabilized lung metastases. She was able to undergo desensitization for 5 cycles until acute development of obstructive pneumonia. In this report of a previously sensitized patient, a type I hypersensitivity reaction was successfully circumvented with 2-staged premedication for oxaliplatin desensitization. The optimum desensitization protocol for oxaliplatin administration in terms of efficacy and tolerability still needs to be defined.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Desensitization, Immunologic; Drug Hypersensitivity; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Premedication; Rectal Neoplasms

To determine the efficacy and safety profile of the combination of cisplatin and 5-fluorouracil modulated both by methotrexate and leucovorin in metastatic/recurrent squamous cell carcinoma of the head and neck.. Twenty-eight patients were treated with cisplatin 40 mg/m2/day continuous infusion for 24 hours on day 1; high-dose 5-fluorouracil 2,000 mg/m2/day and leucovorin 100 mg/m2/day continuous infusion for 48 hours on days 1 and 2; methotrexate 40 mg/m2/day as a bolus infusion 4 hours before 5-fluorouracil and leucovorin on day 1. The treatment was repeated every 2 weeks in a cycle.. The overall response rate was 25%, and 14% of the patients achieved stable disease status. Subgroup analysis demonstrated significantly improved overall survival in the disease-control group (12.0 months vs. 5.3 months, p<0.001). Only 3 (10.7%) patients developed grade 3-4 neutropenia, and none developed grade 3-4 non-hematologic toxicity.. This multiagent-containing regimen has an excellent safety profile and improved survival in disease-control group of patients with metastatic/recurrent squamous cell carcinoma of the head and neck.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Treatment Outcome; Vitamin B Complex

K-Ras mutations predict resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy.. This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths). Liver metastases (n = 93) along with primary tumors (n = 48) were analyzed for K-Ras mutations (codons 12 and 13), p53 mutations (exons 4-9), p53 polymorphism (codon 72), thymidylate synthase (TS) polymorphism (28-bp repeats including G>C mutation), methylenetetrahydrofolate reductase polymorphism (677C>T, 1298A>C), thymidylate synthase (TS) activity, dihydropyrimidine dehydrogenase activity, folylpolyglutamate synthase activity, and p53 protein expression.. Thirty-six of 93 (38.7%) metastases were K-Ras mutated (30 at codon 12 and 6 at codon 13). Mutated primary tumors (16 of 48) matched perfectly with mutated metastases. The additional analyzed tumor markers were not different between K-Ras mutated and wild-type tumors. The objective response rate was 37%: 44.4% in K-Ras mutated versus 32.1% in wild-type K-Ras metastasis (P = 0.27). Low TS activity in metastasis was the only significant predictor of tumor response (P = 0.047). K-Ras status did not influence specific survival.. The present data indicate a perfect concordance of K-Ras mutations between primary and liver metastasis and suggest that any predictive and/or prognostic value of K-Ras mutations in treatments combining anti-EGFR monoclonal antibodies with 5-FU should be exclusively linked to the anti-EGFR agent.

Topics: Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mutation; Neoplasm Metastasis; Polymorphism, Genetic; Treatment Outcome

Although a variety of FOLFOX regimens (5-fluorouracil and L-leucovorin combined with oxaliplatin) are widely used for the treatment of advanced colorectal cancer, the neurotoxicity caused by oxaliplatin is often problematic. The aim of this observational study was to assess the safety and efficacy of a modified version of the FOLFOX6 regimen (mFOLFOX6) when administered using the 'stop-and-go' strategy.. A total of 112 eligible patients treated between June 2005 and July 2007 were identified using the prospective cohort database system of Kyoto University Hospital.. The median follow-up was 16.3 months (range 1.6-33.9), and the response rate was 33.3% (95% CI 14.5-52.2), 40.0% (95% CI 22.5-57.5) and 14.0% (95% CI 3.6-24.3) for patients who received mFOLFOX6 as first-line therapy, second-line therapy and third- or later-line therapy, respectively. The estimated median progression-free survival was 8.7 months (95% CI 2.3-15.1) and 8.2 months (95% CI 7.3-9.1) for patients on first-line and second-line therapy, respectively. The median overall survival was not reached as of April 2008 for the patients on first-line therapy, while it was 27.1 months (95% CI 22.0-32.2) for those on second-line therapy. Severe neurotoxicity occurred in only 4 patients (3.6%).. mFOLFOX6 administered using the stop-and-go strategy significantly reduced oxaliplatin-induced neurotoxicity relative to conventional FOLFOX treatment, without compromising efficacy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Retrospective Studies; Survival Rate; Treatment Outcome

In this study, we investigated the efficacy and toxicity of fluorouracil(FU)+Leucovorin(LV)with oxaliplatin (FOLFOX)and irinotecan(FOLFIRI)for patients with advanced or metastatic colorectal cancer.. Eleven patients with advanced or metastatic colorectal cancer underwent chemotherapy, such as FOLFOX4, mFOLFOX6, and FOLFIRI. Four and 7 patients underwent FOLFOX4 and mFOLFOX6 as a first-line therapy, respectively. Five patients underwent FOLFIRI as a second-line therapy.. The response rate(RR)for FOLFOX4 and mFOLFOX6 as a firstline therapy was 0%(0 of 4 patients)and 71%(5 of 7 patients), respectively. The RR for FOLFIRI as a second-line therapy was 40%(2 of 5 patients). The survival time of the eight patients experiencing CR, PR or SD in the firstline FOLFOX4/mFOLFOX6 or the second-line FOLFIRI is 7 to 27 months. That of the three patients not showing CR, PR or SD is 4 to 8 months. The former is significantly longer than the latter(p=0.0023). Toxicities were paresthesia, neutropenia, thrombocytopenia and general fatigue in FOLFOX4, paresthesia, neutropenia, thrombocytopenia, diarrhea and anaphylaxis in mFOLFOX6, while those were neutropenia, thrombocytopenia, stomatitis and general fatigue in the second-line FOLFIRI.. For advanced or metastatic colorectal cancer, FOLFOX4/mFOLFOX6 followed by FOLFIRI may be effective and comparatively safe treatments.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Salvage Therapy; Tomography, X-Ray Computed

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Body Surface Area; Colorectal Neoplasms; Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Fluorouracil; Humans; Leucovorin; Models, Biological; Neoplasm Metastasis; Time Factors; Treatment Outcome; Vitamin B Complex

We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability.. Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study).. In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR.. Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asia, Eastern; Capecitabine; Chemotherapy, Adjuvant; Colorectal Neoplasms; Deoxycytidine; Europe; Fluorouracil; Gastrointestinal Diseases; Humans; Leucovorin; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Prodrugs; Residence Characteristics; Retrospective Studies; Risk Assessment; Severity of Illness Index; Treatment Outcome; United States; Vitamin B Complex; Withholding Treatment

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Cost-Benefit Analysis; Deoxycytidine; Drug Costs; Economics, Pharmaceutical; Fluorouracil; Hospital Costs; Humans; Infusions, Parenteral; Leucovorin; Models, Economic; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Patient Selection; Research Design; Treatment Outcome; Vitamin B Complex

GOLFIG-1 chemo-immunotherapy is a new translational anticancer regimen based on the combined use of gemcitabine, oxalipatin, levofolinic acid and infusional 5-fluorouracil together with the subcutaneous administration immunoadjuvant cytokines (GM-CSF and ultra low dose IL-2). This regimen, tested in a phase II trial, was safe and very active in patients with metastatic colorectal carcinoma and it has been shown to have powerful immunobiological activity. Treatment with the GOLFIG regimen resulted in the induction of a colon cancer specific cell mediated immune response associated with a significant reduction in the percentage of peripheral regulatory T (T(reg)) cells, a very immunosuppressive lymphocyte subset which is commonly over-represented in cancer patients. These cells are able to prevent the occurrence of autoimmunity in response to immunological stimuli, thus their malfunctioning has been associated with the occurrence of auto-immune diseases but may also be responsible for more efficient anticancer immune reaction. In this manuscript we describe a clinical case concerning a patient with metastatic colon carcinoma who responded to the GOLFIG regimen, showed symptoms of autoimmunity [Discoid Lupus Erythematosus (DLE)] and had a very long survival.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Autoimmunity; Colonic Neoplasms; Deoxycytidine; Female; Flow Cytometry; Fluorouracil; Gemcitabine; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunotherapy; Interleukin-2; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease Progression; Drug Eruptions; ErbB Receptors; Female; Fluorouracil; Humans; Hypertension; Leucovorin; Middle Aged; Neoplasm Metastasis; Treatment Failure

Docetaxel, capecitabine and 5-fluorouracil have been shown to be active in the treatment of metastatic gastric adenocarcinoma. Consistent with this finding, the aim of this study was to test this combination in a clinical trial. Forty-one patients with metastatic gastric adenocarcinoma and a median age of 64 years were recruited for the study. The treatment was based on the administration of docetaxel 60 mg/m2 every 4 weeks, leucovorin 200 mg/m2, 5-fluorouracil 400 mg/m2 bolus, and capecitabine 1000 mg/m2 twice daily on days 1 and 2 every 2 weeks. Patients achieving a clinical benefit were treated, as maintenance immunotherapy, with low-dose interleukin-2 and 13-cis-retinoic acid. The primary end point of this phase II study was the response rate. The secondary end points relied on the evaluation of the immunological parameters, toxicity, and progression-free survival and overall survival. The overall response rate in the 41 evaluable patients was estimated to be 49%. Median progression-free and overall survival was 9.5 and 21.1 months, respectively. Grade 3 and 4 hematological toxicities were neutropenia and thrombocytopenia in 44 and 5% of patients, respectively. A sustained improvement of evaluated immunological parameters with a negligible toxicity profile was observed in the 27 patients treated with interleukin 1-2/13-cis-retinoic acid. Docetaxel in combination with leucovorin, 5-fluorouracil and capecitabine followed by low-dose interleukin 1-2 and 13-cis-retinoic acid is well tolerated, and shows a significant activity in patients with metastatic gastric adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; CD4-CD8 Ratio; Combined Modality Therapy; Deoxycytidine; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Endpoint Determination; Female; Fluorouracil; Humans; Immunotherapy; Killer Cells, Natural; Leucovorin; Lymphocyte Count; Male; Middle Aged; Neoplasm Metastasis; Stomach Neoplasms; Survival Analysis; Taxoids; Vascular Endothelial Growth Factor A

Over the past decade, new cytotoxic and biologic therapies beyond the old standard-of-care, biomodulated fluorouracil (5-FU), have become available for the treatment of metastatic colorectal cancer (mCRC). The introductions of irinotecan (Camptosar), oxaliplatin (Eloxatin), and bevacizumab (Avastin) have prolonged survival, but the optimal use of these new therapies remains to be determined. Issues remain regarding management of toxicities, treatment of elderly patients or those with poor performance status, and the duration of treatment with front-line therapy. This article reviews recent and ongoing studies of newer therapies in an effort to determine the best use of these drugs in the treatment of mCRC. Current data support the front-line use of bevacizumab added to either 5-FU/leucovorin alone or 5-FU/leucovorin in combination with oxaliplatin (FOLFOX/bevacizumab) or irinotecan (FOLFIRI/bevacizumab). If oxaliplatin is used in first-line therapy, oxaliplatin should be discontinued before the development of severe neurotoxicity and be reintroduced or replaced with irinotecan on disease progression. Definitive conclusions on the sequence and duration of front-line therapy and the most effective strategy to ameliorate toxicity await results of ongoing prospective clinical trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Palliative Care

The oxaliplatin/fluorouracil/leucovorin (FOL-FOX regimen) is an effective and generally well-tolerated regimen in Western clinical studies of advanced colorectal cancer. In Japan, oxaliplatin was approved in April 2005.. To evaluate the objective tumor responses and feasibility (toxicities) of FOLFOX regimens (FOLFOX4 and modified FOLFOX6, mFOLFOX6) in a predominantly Japanese population with refractory or advanced colorectal cancer in Japan, 51 consecutive patients with histologically confirmed metastatic colon or rectum cancer who were treated between April 2005 and March 2006 were enrolled in a retrospective study. FOLFOX4 was used for treatment in 39% (first-line, 45%) of these patients, and mFOLFOX6 was used for treatment in 61% (first-line, 61%). Tumor responses were assessed radiologically, and toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 regarding toxicities other than peripheral sensory neuropathy.. The objective response rates (in those who underwent first- or second-line therapy) were 50.0% and 8.7%, respectively. The tumor control rate (partial response [PR] + stable disease [SD]) was 80.4%. There were no toxicity-related deaths. Neutropenia grade 3 was experienced in 20% of patients, and often caused delay in the subsequent treatment course. Mild to moderate cumulative peripheral sensory neuropathy affected 78% of patients. The incidence of hypersensitivity reactions to oxaliplatin in our study was lower than that in reported in Western countries.. Both FOLFOX regimens have good efficacy in refractory or advanced colorectal cancer in a Japanese population, with an acceptable overall toxicity profile.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies; Treatment Outcome

Recent data have shown the efficacy of cetuximab/Folfiri regimen in patients with chemotherapy-resistant metastatic colorectal cancer. In the literature there are no data about this treatment in HIV-positive patients with metastatic colorectal cancer. At the Aviano Cancer Center, we used the cetuximab/Folfiri regimen and concomitant HAART in an HIV-positive patient with metastatic colorectal cancer. The patient experienced acceptable non-hematological toxicity, without any opportunistic infection and his HIV infection was kept under control. This case suggests that, in the HAART era, a multidisciplinary approach can be offered to HIV patients with advanced cancer when they have good performance status, resulting in efficacious control of the HIV infection.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; HIV Infections; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis

The objectives of the present study were to evaluate the efficacy and safety of an outpatient-basis chemotherapy of oxaliplatin, 5-fluorouracil, and leucovorin as the first-line treatment for patients with advanced colorectal cancer. Forty-three histologically confirmed patients with metastatic or recurrent colorectal cancer were enrolled. The chemotherapy consisted of oxaliplatin 85 mg/m(2) as a 2-hr infusion on day 1, plus leucovorin 30 mg/m(2) over 10 min, followed by bolus 5-fluorouracil 400 mg/m(2) and an 8-hr infusion of 5-fluorouracil 600 mg/m(2) on days 1 and 2 (modified FOLFOX4), all of which were administered on an outpatient basis every 2 weeks. The median age was 58 yr (range 33-72 yr), and 25 (58.1%) patients had metastatic diseases. Eventually, 39 patients were assessable for efficacy and all assessable for toxicity. Four (9.3%) complete responses and 11 (25.6%) partial responses were confirmed, giving an overall response rate of 34.9% (95% CI; 20.0-49.7%). The median time to progression and median overall survival for all patients was 6.1 months and 17.4 months, respectively. Grade 3/4 neutropenia occurred in 2 patients (4.7%) and febrile neutropenia was observed in 1 patient (2.3%). Modified FOLFOX4, an outpatient-basis regimen, was found to be well-tolerated and effective as the first-line chemotherapy in patients with advanced colorectal cancer.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Outpatients; Oxaliplatin; Recurrence

A combination of oxaliplatin and infusional fluorouracil/leucovorin (FOLFOX4) is one of the standard regimens for palliative and adjuvant chemotherapy for colorectal cancer. However, the feasibility of FOLFOX4 for Japanese patients has not been determined. We conducted this prospective study to evaluate the feasibility of FOLFOX4.. Previously treated or untreated patients with unresectable metastatic colorectal cancer were enrolled. The primary endpoint was the rate of completion which was defined as completion of the first 4 cycles with relative dose-intensity of oxaliplatin of 80% or higher.. Of the 32 enrolled patients, 31 received FOLFOX4. Twenty-four patients (75%) had received prior chemotherapy. The rate of completion of the first four cycles was 87% (27/31; 95% CI, 70.2-96.4%). With the median number of cycles of nine (range, 1-26), grade 3 or 4 hematological toxicity and non-hematological toxicity were seen in 12 (39%) and 5 (16%) patients, respectively. Grade 1 or 2 sensory neuropathy was seen in 28 patients (90%), but no grade 3 or 4 neuropathy was seen. Grade 1 or 2 allergic reaction was seen in five patients (16%). One patient developed fatal interstitial pneumonitis and died of respiratory failure. Objective response rate was 28.6% (6/21; 95% CI, 11.3-52.2%) in the patients with measurable lesions. Median progression-free survival was 6.5 months (95% CI, 4.6-8.5 months) in all patients.. The completion rate of the first four cycles was as high as expected with manageable toxicity, although fatal pneumonitis developed in one case. FOLFOX4 is feasible for Japanese patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Feasibility Studies; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Drug Administration Routes; Economics, Medical; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Time Factors; Treatment Outcome

Active anticancer drugs and/or combination regimens for the treatment of patients failing oxaliplatin, irinotecan and 5-fluorouracil are desperately needed. In this analysis we describe the safety and efficacy of the combination of mitomycin C, UFT and leucovorin in such an extensively pretreated patient population. Between January 2002 and June 2004, a total of 41 patients were treated with mitomycin C (8 mg/m on day 1) and UFT (350 mg/m)+ leucovorin (90 mg) both divided into three daily doses from day 1 to day 14 every 4 weeks. All patients had failed prior first-line and second-line treatment with oxaliplatin, irinotecan and 5-fluorouracil. The aim of this retrospective analysis was to evaluate the efficacy and safety data of this potential salvage therapy regimen. Thirty-nine patients were evaluable for the response. The overall response rate (intent-to-treat) was 7.3% (95% confidence interval, 2.5-19.4%) and disease stabilization was achieved in 29.3%. Median time to progression was 2.5 months (range, 1.5-13.5) and median overall survival was 6 months (range, 1.5-26). Myelosuppression was the most frequent side effect. Grade 3 hematotoxicity, however, was observed in only three patients. The most common nonhematological toxicities consisted of mild and reversible nausea, emesis and diarrhea; again, severe symptoms were only occasionally seen. These data show that the combination of mitomycin C/UFT/leucovorin is safe and active in about one-third of patients in terms of abrogation of progression in extensively pretreated metastatic colorectal cancer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease Progression; Disease-Free Survival; Female; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Neoplasm Metastasis; Rectal Neoplasms; Retrospective Studies; Salvage Therapy; Tegafur; Uracil

FOLFOX-4 (folinic acid/5-fluorouracil/oxaliplatin) chemotherapy is used to treat patients with colorectal liver metastases. We aimed to assess hepatic histopathological responses to neoadjuvant FOLFOX-4 chemotherapy in patients with colorectal liver metastases. We selected all patients (n = 54) treated with FOLFOX-4 for colorectal liver metastases between June 2002 and June 2005. Only 25 underwent hepatectomy and formed the study group. Histological responses were assessed in the study group and a matched control group (n = 25) that did not receive neoadjuvant chemotherapy. The median (IQR) body mass index in the study and control groups was 24 (22-26) and 24 (23-25) kg/m(2), respectively, (P = NS). Complete histological resolution of tumour occurred in six (24%) patients in the study group. Median residual tumour cellularity was less (35 vs 70%) and fibrosis greater (50 vs 5%) in patients in the study group when compared with controls (P < 0.001). The liver surrounding the tumour was steatotic in 17 (68%) patients in the study group and five (20%) controls (P = 0.001). Hepatic sinusoidal dilatation was more pronounced in patients in the study group than in controls (P < 0.001). The response to FOLFOX-4 was associated with tumour necrosis, fibrosis and inflammation. More than two thirds of patients undergoing hepatectomy after FOLFOX-4 had steatosis despite being non-obese.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fatty Liver; Female; Fibrosis; Fluorouracil; Hepatectomy; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Colorectal Neoplasms; Drug Delivery Systems; ErbB Receptors; Evidence-Based Medicine; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Nurse's Role; Oncology Nursing; Organoplatinum Compounds; Practice Guidelines as Topic; Vascular Endothelial Growth Factor A

The FOLFIRI regimen (irinotecan in combination with bolus and continuous infusion of 5-FU and l-LV) and FOLFOX regimen (oxaliplatin/5-FU/LV therapy) are now standard chemotherapy for metastatic colorectal cancer in Western countries. Combining those regimens, a median overall survival time (MST) of over 20 months has been reached. However, adverse reactions related to those regimens have included deteriorating patient quality of life (QOL). Here, we report a case of metastatic rectal cancer showing a complete response (CR) to cycle 4 in FOLFIRI regimen, while maintaining a CR status for over 11 months and good QOL, as a result of chemotherapy with 4 cycles of FOLFIRI followed by UFT.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Rectal Neoplasms; Tegafur; Uracil

Liver metastasis is an important prognostic factor in colorectal cancer. The efficacy of resection of metastatic lesions in liver metastasis of colorectal cancer is also widely recognized. However, studies on treatment methods of unresectable cases have not been sufficient and obtaining complete remission (CR) for liver metastasis is rare with chemotherapy. Selection of reliable chemotherapy for unresectable liver metastasis is an urgent necessity. The usefulness of oxaliplatin, 5-flurouracil and leucovorin combination therapy (FOLFOX) has recently been reported, but CR of liver metastasis is rare. The current status and new therapeutic significance of FOLFOX therapy are discussed based on the literature of colorectal cancer chemotherapy to date, and the clinical experience in which we obtained CR for liver metastasis is reported. The patient had stage IV rectal cancer, perforative peritonitis, pelvic abscess and simultaneous multiple liver metastasis. The patient underwent an emergency operation using the Hartmann's procedure. Liver metastasis is considered to be a prognostic factor and FOLFOX was selected as the postoperative chemotherapy, CR of the liver metastasis was obtained. FOLFOX was suggested to have new clinical significance in oncologic emergencies against unresectable liver metastasis in colorectal cancer and should serve as adjuvant chemotherapy that will contribute to improvement of treatment results.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonoscopy; Colorectal Neoplasms; Contrast Media; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Remission Induction; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

The clinical efficacy and safety of irinotecan plus infusional fluorouracil/l-leucovorin (FOLFIRI) in patients with fluoropyrimidine-resistant metastatic colorectal cancer were studied retrospectively. 20 patients were treated with FOLFIRI at our hospital between October 2003 and November 2005. The objective overall response rate was 28% (5/18; 95% confidence interval, 9.7-54%). The disease control rate (CR+PR+SD) was 61%. The most frequent grade 3 to 4 adverse event was neutropenia, and it was seen in 50%. Non-hematological toxicities were mild. The median survival time was 11 months. The 1-year survival rate was 34%. This study showed the activity and safety of FOLFIRI in practice.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Survival Rate; Treatment Outcome

The cost of chemotherapy has dramatically increased in advanced colorectal cancer patients, and the schedule of fluorouracil administration appears to be a determining factor. This retrospective study compared direct medical costs related to two different de Gramont schedules (standard vs. simplified) given in first-line chemotherapy with oxaliplatin or irinotecan. This cost-minimization analysis was performed from the French Health System perspective. Consecutive unselected patients treated in first-line therapy by LV5FU2 de Gramont with oxaliplatin (Folfox regimen) or with irinotecan (Folfiri regimen) were enrolled. Hospital and outpatient resources related to chemotherapy and adverse events were collected from 1999 to 2004 in 87 patients. Overall cost was reduced in the simplified regimen. The major factor which explained cost saving was the lower need for admissions for chemotherapy. Amount of cost saving depended on the method for assessing hospital stay. In patients treated by the Folfox regimen the per diem and DRG methods found cost savings of Euro 1,997 and Euro 5,982 according to studied schedules; in patients treated by Folfiri regimen cost savings of Euro 4,773 and Euro 7,274 were observed, respectively. In addition, travel costs were also reduced by simplified regimens. The robustness of our results was showed by one-way sensitivity analyses. These findings demonstrate that the simplified de Gramont schedule reduces costs of current first-line chemotherapy in advanced colorectal cancer. Interestingly, our study showed several differences in costs between two costing approaches of hospital stay: average per diem and DRG costs. These results suggested that standard regimen may be considered a profitable strategy from the hospital perspective. The opposition between health system perspective and hospital perspective is worth examining and may affect daily practices. In conclusion, our study shows that the simplified de Gramont schedule in combination with oxaliplatin or irinotecan is an attractive option from the French Health System perspective. This safe and less costly regimen must compared to alternative options such as oral fluoropyrimidines.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Health Care Costs; Health Services; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies

Thrombocytopenia developing in the course of chemotherapy for malignant disease is usually attributed to drug-induced marrow suppression and/or marrow replacement by tumor. We describe two patients who developed severe thrombocytopenia and hemorrhagic symptoms while being treated with oxaliplatin, 5-fluorouracil, and leukovorin for metastatic colon cancer in whom platelet destruction appears to have been caused by oxaliplatin-dependent antibodies specific for the platelet glycoprotein IIb/IIIa complex (alpha(IIb)/beta(3) integrin). Drug-induced immune thrombocytopenia (DITP) should be considered in patients who experience a sudden, isolated drop in platelet levels while being treated with chemotherapeutic agents, especially when adequate numbers of megakaryocytes are present in the bone marrow.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Autoantibodies; Bone Marrow Cells; Carcinoma; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Megakaryocytes; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Purpura, Thrombocytopenic, Idiopathic; Vitamin B Complex

Ferredoxin reductase (FDXR) is a putative contributor to p53-mediated apoptosis from 5-fluorouracil (5-FU) through the generation of oxidative stress in the mitochondria. However, the influence of FDXR gene expression levels on the outcome of 5-FU chemotherapy has been relatively little studied. The aim of this study is to investigate the association between FDXR gene expressions and the clinical outcome when treated by 5-FU chemotherapy, as well as the correlation of FDXR gene expressions and p53 mutation.. Pre-chemotherapeutic fresh frozen samples of 33 patients with metastatic colorectal cancer, who received bolus 5-FU and leucovorin (LV) as first line chemotherapy, were studied. FDXR gene expression and p53 mutation were evaluated by real-time RT-PCR and direct sequencing, respectively.. FDXR gene expression was significantly higher in responding tumors compared with non-responding ones (P=0.0379). Patients with FDXR values above the cutoff value of 13.52 had a statistically longer survival than those with FDXR gene expressions below the cutoff value (P=0.0148). The 9 tumors with wild-type p53 had statistically higher FDXR gene expressions than the 14 tumors with mutant-type p53 which had sequence alterations within the "hot spot" codons, the L2-L3 loops, or frameshift (P=0.0463).. FDXR gene expression did not affect clinical outcome in patients with wild-type p53 tumors, whereas, among patients with p53 mutant-type tumors, patients with tumors with low FDXR gene expression had a worse outcome than those with a high FDXR gene expression (P=0.0200). FDXR gene expression, which is regulated at least in part by p53, is associated with both response and survival when metastatic colorectal cancer is treated with 5-FU plus LV. In addition, analysis of p53 mutation combined with FDXR gene expression might be useful in estimating the outcome in 5-FU-treated patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; DNA Mutational Analysis; Ferredoxin-NADP Reductase; Fluorouracil; Frameshift Mutation; Gene Expression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Middle Aged; Mutation, Missense; Neoplasm Metastasis; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Survival Analysis; Treatment Outcome; Tumor Suppressor Protein p53

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Monitoring; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Nurse's Role; Oncology Nursing; Organoplatinum Compounds; Patient Care Planning; Practice Guidelines as Topic; Salvage Therapy

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Gene Expression Profiling; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

The question of continuous versus intermittent chemotherapy for patients with metastatic colorectal cancer has been an ongoing issue of debate for determining the optimum duration of treatment. The results from 2 major trails addressing this issue were recently presented at the 2006 Annual Meeting of the American Society of Clinical Oncology. The OPTIMOX2 trial evaluated the efficacy and safety of oxaliplatin reintroduction after a complete chemotherapy-free interval or maintenance therapy in patients with previously untreated disease. The GISCAD (Italian Group for the Study of Digestive Tract Cancer) study investigated the utility of intermittent versus continuous irinotecan-based chemotherapy. Both studies demonstrated that chemotherapy can be administered intermittently without affecting the overall efficacy of treatment.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Multicenter Studies as Topic; Neoplasm Metastasis; Organoplatinum Compounds; Randomized Controlled Trials as Topic; Survival Analysis; Thymidylate Synthase; Vitamin B Complex

In order to discuss the role of preoperative chemotherapy for colorectal liver metastases, which is used frequently before hepatic resection, even in patients with resectable disease at presentation, we herein report the development of two complications, partial portal vein thrombosis and hepatic steatosis with lobular inflammation, during the course of preoperative chemotherapy with FOLFIRI plus bevacizumab for colorectal liver metastases, which recognition led to timely discontinuation of chemotherapy as well as a change in the surgical strategy to resect the tumors and the damaged liver through advanced techniques. We conclude that duration of treatment and drug doses and combinations may impact the development of chemotherapy-induced liver injury. Surgeons and medical oncologists must work together to devise safe, rational, and oncologically appropriate treatments for patients with multiple colorectal liver metastases, and to improve the understanding of the pathogenesis of chemotherapy-induced liver injury.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Fatty Liver; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Metastasis; Portal Vein; Venous Thrombosis

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Data Interpretation, Statistical; Disease-Free Survival; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Pulse Therapy, Drug; Sample Size; Survival Analysis; Treatment Outcome

Replacing infusional 5-fluorouracil (5-FU) leucovorin (LV) with oral capecitabine would be more convenient to patients, because it would lead to reduced hospital chair time and infusion-related toxicities. Previous trials with oral capecitabine-based regimens (other than XELOX [capecitabine/oxaliplatin]) have failed to demonstrate the equivalent efficacy of capecitabine based regimens to various 5-FU/oxaliplatin regimens (nonstandard FOLFOX [5-FU/LV/oxaliplatin] combinations); of note, these trials did not use the XELOX and standard FOLFOX regimens. An international phase III trial (NO16966) was initiated to demonstrate the noninferiority of XELOX to FOLFOX4 for the first-line treatment of metastatic colorectal cancer. The protocol was later amended to compare bevacizumab and chemotherapy versus placebo and chemotherapy. The efficacy data showed that XELOX was as effective as FOLFOX4 (progression-free survival [PPS; intent-to-treat population]: hazard ratio [HR], 1.04; 97.5% confidence interval, 0.93-1.16). Also, bevacizumab/chemotherapy(pooled with XELOX or FOLFOX) significantly prolonged PPS (HR 0.83; p=0.0023) compared with placebo and chemotherapy (XELOX/FOLFOX). In subgroup analysis, the addition of bevacizumab to XELOX (9.3 months vs. 7.4 months. HR.0.77; P=0.0026) and FOLFOX4(9.4 months vs. 8.6 months; HR, 0.89; P = 0.1871) prolonged PFS compared with respective placebo arms; however, it did not show statistical significance with the FOLFOX4 regimen. The adverse events were manageable and comparable between treatment arms.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate

The results of a randomized comparison study (N9741) showed that oxaliplatin and infusional fluorouracil (FU) (FOLFOX) was superior to the previous standard of care in the United States, irinotecan and bolus FU (IFL), as first-line therapy for patients with metastatic colon carcinoma. The trade-offs between costs and survival for these two regimens have not been explored.. A post-hoc, incremental cost-effectiveness (ICE) projection using simulated cohorts of patients starting FOLFOX or IFL was tracked for major clinical events, toxicities, and survival. Recurrence and survival risks were based on clinical trial data. Resource use was projected using observed dose intensity, duration of therapy, delays in therapy, and toxicities Grade > 2 in N9741. The frequency, costs, and consequences of second-line therapy were examined. The time frame was 5 years, and the perspective was that of Medicare as a third-party payer.. Initial treatment with FOLFOX versus IFL had an average incremental cost of dollars 29,523, a survival benefit of 4.4 months, and an ICE of dollars 80,410 per life year (LY), dollars 111,890 per quality-adjusted LY, and dollars 89,080 per progression-free year. By using the 95% confidence interval for the time to progression observed in N9741, the ICE associated with FOLFOX ranged from dollars 121,220 to dollars 59,250 per LY. In the clinical trial, dose delays and skipped doses were frequent. If progression-free patients were treated without delay for the first year or lifetime, then the ICE for FOLFOX increased to dollars 117,910 and dollars 222,200 per LY, respectively. The ICE increased to dollars 84,780 per LY when the model incorporated a revised IFL schedule with lower early toxicity and similar rates of treatment with second-line regimens.. FOLFOX provided substantial benefits that incurred substantial additional costs. The ICE for FOLFOX fell into the upper range of commonly accepted oncology interventions in the context of the United States healthcare system.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Costs; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma; Case-Control Studies; Cisplatin; Combined Modality Therapy; Disease Progression; DNA, Viral; Fluorouracil; Genotype; Herpesvirus 4, Human; Humans; Infusions, Intravenous; Leucovorin; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Polymerase Chain Reaction; Sensitivity and Specificity; Survival Analysis

Irinotecan, in combination with 5-fluorouracil (5-FU) and a high dose of leucovorin (LV), known as FOLFIRI regimen, has shown activity in recurrent or metastatic colorectal cancer. Therefore, we evaluated the efficacy and safety of irinotecan, 5-FU and a low dose of LV (modified FOLFIRI) as a first line of therapy for patients with relapsed or metastatic colorectal cancer.. Between January 2002 and October 2004, 44 patients with histologically confirmed recurrent or metastatic colorectal cancer were enrolled. The chemotherapy regimen schedule consisted of 180 mg/m2 of irinotecan being administered intravenously (i.v) on Day 1, 400 mg/m2 of 5-FU via i.v bolus with 600 mg/m2 of continuous infusion for 22 hrs on both Day 1 and 2, and 20 mg/m2 of leucovorin on both Day 1 and 2 , repeated every two weeks.. The overall response rate was 47.8%. Of the 40 evaluated patients, one had CR (2.3%) and 20 had PR (46.5%). Toxicities were mild and easily manageable. Three patients experienced 23 episodes of Grade 3/4 leukopenia., Only one patient developed Grade 3/4 diarrhea. None experienced Grade 3/4 thrombocytopenia.. Modified FOLFIRI with a low dose of LV is an effective and tolerable regimen for patients with recurrent or metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local

Jejunal adenocarcinoma is rare, often presenting late with widespread intraperitoneal disease. Intraperitoneal chemotherapy (IPC) has been shown in non-randomized studies to improve the survival of patients presenting with intraperitoneal metastases from carcinoma of the colon, appendix and stomach and in primary peritoneal malignancies including mesothelioma and pseudomyxoma peritonei, providing that adequate operative cytoreduction can be performed. A case is presented of obstructive jejunal adenocarcinoma in which 19 intraperitoneal deposits were excised. The patient was treated successfully with immediate postoperative IPC followed by systemic chemotherapy. This condition is reviewed along with the rationale for IPC.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Infusions, Parenteral; Intestinal Obstruction; Jejunal Neoplasms; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Peritoneal Neoplasms